The Progress Of 1,3,5-Triazine Derivatives As Anticancer Drug

Abstract: Studies on the various types of cancer drugs is one of the important areas in clinical research. Identification and characterization of potential molecules from various sources have been carried out in the past and their relationship with the enzymes which are involved in cancer is becoming increasingly interesting. The 1,3,5-triazine skeleton is classical and one of the most interesting chemical core structures for biological activity, many triazine derivatives have been developed as anticancer agents . To our knowledge, few studies on triazines has been reported to date. In this review, we have highlighted various inhibitors with 1,3,5-triazine core which targeting diffirent kinases. The mechanism of action and characterization of these anticancer compounds are discussed in this communication.
Keywords: 1,3,5-triazine,inhibitors, cancer, kinases , antitumor
Introduction: Triazine-containing compounds, particularly 1,3,5-triazines, have received considerable attention owing to their broad biological activities, such as antitumor activity involving different targets.1,3,5-triazine derivatives containing various amino groups at position 2, 4 or 6, such as tretamine, furazil and dioxadet, have been known as anticancer drugs.Hexamethylmelamine (HMM) 1 was discovered as an effective agent against breast, lung, and ovarian cancers, but unfortunately it causes many serious adverse effects. Compound 2 was reported by Moon et al. as a microtubule destabilizing entity with potent growth inhibition against U937 cells (GI50 = 1??M). Leftheris et al. found compound 3 was a potent inhibitor of p38 MAP kinase with oral activities. Compound 4 was recently investigated by Baindur et al. as potent VEGF-R2 (KDR) tyrosine kinase inhibitor [1]. From the reported structures, we notice that there is a common feature for compounds to exhibit antitumor activities by introducing structural units of various arylamino groups into the triazine scaffold. Based on the above findings and the availability of abundant tri-substituted 1,3,5-triazine compounds, we will strive to screening our compounds on selected cancer targets,such as PI3Ks, ROCKs and so on.

1 Target PI3K kinases
Phosphoinositide 3 kinases (PI3Ks) are lipid kinases that phosphorylate the 3-hydroxy group of phosphoinositides, first discovered by L. C. Cantley in the 1980s.The PI3K family is consist of three classes of highly conserved proteins with different substrate preferences and regulation mechanisms. Class I PI3Ks are the most well characterized PI3Ks, which are heterodimers comprising a catalytic subunit (p110??, p110??, p110??and p110??) and a regulatory subunit. Class II and III PI3Ks share high sequence homology in kinase domains and have a similar phosphorylation capability to that of class I PI3Ks, while their physiological functions are less well understood. Besides, PI3K-related protein kinases (PIKKs), such as the mammalian target of rapamycin (mTOR) and DNA dependent protein kinase (DNA-PK), are usually referred to as class IV PI3Ks because their catalytic core is similar to PI3Ks[2]. Accumulating evidence suggests that the PI3K pathway is among the most widely activated signaling pathways in cancer, and PI3K is a well established target for anticancer therapy.

Various types of PI3K inhibitors, including molecules that inhibit just the PI3K family with different selectivities against the four isoforms of class I PI3Ks and those that knock down the PI3K family and other downstream enzymes, such as mTOR, have been disclosed. The clinical arena today is becoming increasingly competitive as more and more PI3K inhibitors are in the race to reach the market for cancer treatment. This review outlines the current landscape of the development of small molecule PI3K inhibitors with a focus on progress made in recent years.
1.1 pan inhibitor of class I PI3Ks
ZSTK474(compound 5)[2-(2-difluoromethyl benzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine] was first reported as a potent ATP competitive pan class I PI3K inhibitor in 2006'it is an orally available PI3K inhibitor with IC50 values of 16, 44, 5 and 49 nM against p110??, p110??, p110??and p110??, respectively.[2] ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474 (3) .ZSTK474 and several other 1,3,5-triazine derivatives were previously synthesized as antitumor agents with antiproliferative activity, and later identified as a PI3K inhibitor. Compound 6 was reported by Gordon W et al. displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue (compound 7) against all three class Ia PI3-kinase enzymes (p110??, p110??, and p110??) and also displayed significant potency against two mutant forms of the p110?? isoform (H1047R and E545K)(4). Not surprisingly, synthetic work on PI3K inhibitors based on the triazine or triazine-benzimidazole core structure has continued recently though not at the same pace as new reports based on purine/pyrimidine core structures.(5)

Starting from the dual PI3K/mTOR inhibitor 8, Adrian L et al. [6] identified compound 9 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 9 demonstrated a robust PD'PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

Molecular modeling suggestions that the addition of appropriate substituents at the 4- and 6-positions of the benzimidazole ring of ZSTK474 could result in tighter binding derivatives.Compound 10 was identified as a very potent analogue by Michelle S et al. [7]. On the basis of cell based studies and the pharmacokinetic data, 10 was tested in a U87MG human glioblastoma xenograft model, where it caused a significant reduction in tumor growth at MTD. However, despite the good pharmacokinetics and promising anticancer efficacy of 10, its poor solubility properties prevented it from being well tolerated in vivo.

Mark H et al. reported the optimization of compound 11, which led to the design and synthesis of pyridyltriazine 12, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile [8]. Compound 12 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model with an EC50 of 228ng/mL. Furthermore, 12 potently inhibited tumor growth in a U87 MG glioblastoma xenograft model (ED50 = 0.6 mg/kg). On the basis of its excellent pharmacokinetic properties and in vivo efficacy, compound 12was selected for further evaluation as a clinical candidate for the treatment of cancer and was designated AMG 511. A more detailed biological profile of AMG 511 will be reported in due course.

1.2 Selective inhibitor of class I PI3Ks
1.2.1 PI3K??
In recent years, isoform-selective inhibitors have emerged, and compounds such as BYL719, a PI3K?? selective inhibitor, and CAL-101, a PI3K??-specific inhibitor, are now in phase I/II clinical trials.BKM120 [2] (compound 13) is a 2,4-bismorpholinopyrimidyl PI3K inhibitor with an IC50 value of 0.03??M against PI3K??and BKM-120 is currently undergoing Phase III clinical trials. Biological and pharmacokinetic evaluations have revealed that BKM120 exhibited good potency against several types of tumor cell lines, significant pAkt inhibition and tumor growth inhibition against the U87MG glioma model, and favorable pharmacokinetic properties and safety profile. Besides, BKM120 has been shown to inhibit tumor growth in mouse orthograft models. BKM120 has demonstrated preliminary antitumor activity in a phase I dose-escalation study.

In 2012, a series of pyridinyl substituted triazines was reported by Smith, A. et al. with compound 14 being most active and most selective for PI3Ka over mTOR[9]. Lead compound 14 provided orally demonstrated robust inhibition of HGF-induced Akt phosphorylation in liver at both 25 and 75 mg/kg for 8 h. The higher dose maintained inhibition for 24 h at 64%. Stabilization of U-87 tumor growth was achieved at 25 mg/kg without significant toxicity [10].

Also in 2012, Wurz et al. reported new amino pyridinyl triazines where the amino group in the amino pyridine had been substituted by a variety of pyridinyl sulfonamides [11].

Mark E. Welker , George Kulik, Bioorg. Med. Chem. 21 (2013) 4063'4091, Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

1.2.2 PI3K??
A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified by Jo-Anne Pinson etal. as potent and isoform-selective inhibitors of PI3K??[12]. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3K??, while their D-congeners favored PI3K??. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3K??-selective inhibitors, distinguishing this class from other reported PI3K??-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
In the wild-type enzyme, 15 adopted the anticipated pose closely overlaying the reported pose of ZSTK474 in PI3K??and making a specific interaction of the free amine with D862.Compound 15 showed strong cellular inhibition of Akt phosphorylation relative to the direct enzyme assay with IC50 values <10 nM, and showed comparable potency to ZSTK474 in cell growth despite both lower potency at PI3K?? and poor potency at the other isoforms.

1.3 mTOR inhibitors
The mammalian target of rapamycin (mTOR) is a member of the phosphoinositide-3-kinase (PI3K)-related kinases (PIKKs), high molecular mass serine/threonine protein kinases. mTOR is frequently upregulated in cancer and is a clinically validated cancer treatment target.[13] The mTOR pathway senses the cellular availability of nutrients and energy, serves as a downstream regulator of growth factor signaling, and is ultimately responsible for mediating cell functions mTOR functions through two distinct multi-protein complexes, each defined by the interaction of mTOR with either Raptor (regulatory-associated protein of mTOR) as in the case of mTORC1 or Rictor (rapamycininsensitive companion of mTOR) as in the case with mTORC2. mTOR complex 1 (mTORC1) acts as an integral participant in translation and cell growth by phosphorylation of substrates 4EBP1 and S6K, whereas mTOR complex 2 (mTORC2) acts to fully activate signaling through AKT by phosphorylation of S473. Both complexes play critical roles in the PI3K/AKT cascade, a pathway wherein mutations within its signaling components are frequently present in cancer cells. The mTOR is also involved in the signaling pathways of several types of cancers such as renal cell carcinoma, lung cancer, breast cancer, colorectal cancer, and neuroendocrine tumors (Guertin and Sabatini, 2005; Yu et al., 2009). The mTOR kinase therefore became the most attractive target of cancer in the recent years (Huang and Houghton, 2003). [14]
In the preceding Letter, Jeroen C. Verheijen et al. presented the design and synthesis of di-(3-oxa-8-azabicyclo [3.2.1]octan-8-yl)-arylureidophenyl-triazines as potent and selective mTOR inhibitors[15]. Compound 16 is a highly potent and selective inhibitor with excellent activity in murine models of human tumor xenografts. Although 16 displayed excellent stability in nude mouse microsomes (t1/2 >30 min), its clinical development was precluded by its rapid degradation by human microsomes (t1/2 <5 min). The discrepancy between microsomal stability in the pre-clinical efficacy species (nude mouse) and the target species (human) suggests that the CYP isoforms responsible for the major metabolic pathways differ between these two species.
A representative inhibitor, compound 17, displayed potent and selective in vivo inhibition of mTOR leading to efficacy in murine tumor xenograft models at unprecedentedly low doses. Based on its excellent potency, selectivity over PI3K-a and microsomal stability across different species, compound 17 was selected for further evaluation. First, we explored whether 10 was selective over other kinases in addition to PI3K-??. The IC50 against another PI3K isoform, PI3K-??, was 1256 nM (2730-fold selective). In addition, when 17 was screened against an in-house panel of 21 kinases, none of them were inhibited at IC50s below 50??M (>100,000-fold selectivity). In addition to its excellent stability in human microsomes, 17 was highly stable in human hepatocytes as well, as evidenced by low clearance (0.0083 mL/min/million cells) and a high half-life (>60 min). Finally, the potential for cardiac effects and drug'drug interactions was explored.

Compound 18 which were selective for mTOR inhibition over PI3K inhibition were reported in 2011[16]. In tissue culture experiments this compound inhibited proliferation of 18 cancer cell lines with IC50 under 1 ??M. In vivo tests demonstrated inhibition of HGF-stimulated Akt phosphorylation in liver at 30 mg/kg and phosphorylation of S6RP at 100 mg/kg.

Emily A et al. [17] have reported that starting from triazine-benzimidazole 19, which had less desirable PK properties, modifications were made to the central benzimidazole ring to improve solubility. This effort resulted in triazine-imidazopyridine 20, which demonstrated improved solubility and bioavailability when compared to 19. While this outcome was encouraging, the triazine-imidazopyridine series still suffered from high in vivo clearance that was not predicted by in vitro liver microsome experiments. Inhibitor 21 is representative of this SAR change and revealed that although occupation of the ribose pocket with a pyrimidine moiety somewhat mitigated the loss of potency attributed to the methyl pyrazole, the solubility and in vivo PK properties were not improved; furthermore 21 failed to inhibit mTOR activity in the cellular p4EBP1 assay. The high clearance observed for 21 revealed that blocking only one site of glucuronidation was not sufficient to improve the total clearance of these inhibitors. We speculated that the high in vivo CL of 21 was likely a result of shifting the primary site of glucuronidation from the pyrazole to the triazine.

Compound 22, which inhibited phosphorylation of mTOR substrate 4EBP1 in a Lantha-Screen enzyme assay with an IC50 = 97 nM. It was also moderately potent in two U-87 cellular assays that measure the phosphorylation of 4EBP1 (at T37/46, downstream of mTORC1) and AKT (at S473, which is downstream of mTORC2). Compound 23, which demonstrated the best combination of mTOR potency, selectivity over other kinases and pharmacokinetic properties was tested in vivo in our mouse pharmacodynamic assay. Inhibitor 23 showed dose-dependent inhibition of mTOR kinase activity, showing up to 83% inhibition of downstream substrate Pakt [18].

Arie Zask et al. previously reported that bridged morpholines on pyrazolopyrimidine (24) and thienopyrimidine (25) scaffolds with a para-ureidophenyl substituent led to potent mTOR inhibitors with greater selectivity for mTOR versus PI3K than the corresponding morpholine containing analogs. Incorporation of bridged morpholines onto the monocyclic triazine scaffold bearing a ueridophenyl group gave potent and selective mTOR inhibitors. 26 was shown to selectively suppress mTOR biomarkers both in vitro in MDA361 cells and in vivo in nude mice bearing U87MG tumors [13].

Several compounds with a central triazine core and a morpholine substituent like 27 were found to be sub-micromolar mTOR inhibitors. 27 exhibited a fivefold selectivity towards mTOR compared to PI3K??, has a lower molecular weight of 356 Dalton and as a result higher mTOR ligand efficiency of 0.34 kCal/mol/HA. Anders Poulsen et al. [19] have reported that compound 28 has a slightly better inhibitory potency towards mTOR, high LE of 0.39 kCal/mol/HA and is 60 fold selective towards mTOR.

The 2,5-bridged morpholine derivative (29) showed good potency against mTOR. 29 displayed IC50s of 250 and 300 nM, respectively, in these cellular assays. Use of (R)-3-methylmorpholine, resulted in enhanced activity against mTOR and a corresponding increase in cellular activity. The activity of the 3-pyridyl urea, bis-(R)-3-methylmorpholine 30 prompted a thorough investigation of alternative urea derivatives [20].

BMCL-200908069-1(compound 31) displays potent antitumor activity with an mTOR inhibitory concentration 50%(IC50) of 0.27 ??mol/L. Compound 32 was reported by HUANG Qiang et al. [21]and it is more active than BMCL-200908069-1 against HT-29, H460 and MDA-MB-231 cancer cell lines.Wufu Zhu et al.[22]reported that compound 33(with IC50 values of 0.05??M) was evaluated for mTOR activity by LANCE, exhibited significant antiproliferative activity and high selectivity against the H460 cancer cell line. compound 33, possessing a cyano group substituted at the C-3 position of the benzene ring, showed strong antiproliferative activity against the H460, HT-29, and MDA-MB-231 cell lines with IC50 values of 0.05, 6.31, and 6.50 ??M, which were 190.4, 4.6, and 5.6 times more active than compound 31 (9.52, 29.24, and 36.21??M), respectively.

2 PI3K/mTOR dual inhibitors
More than 50% of all solid tumors have gene mutations, deletions, or amplifications that lead to up regulated PI3K/Akt/mTOR signaling. Therefore, blocking the PI3K/Akt/mTOR signaling pathway by inhibiting both PI3K lipid and mTOR serine/threonine kinase activity provides an innovative strategy for cancer therapy [23]. Dual PI3K/mTOR inhibitors also mitigate the feedback activation of PI3K signaling caused by selective mTORC1 inhibitors (i.e., rapamycin and its analogs), and because of this they may yield greater therapeutic benefit in cancer patients.
PKI587 (PF-05212384, 34) is recently emerged PI3K'm TOR dual inhibitor. PKI587 (PI3K??, PI3K??and mTOR, IC50 values of 0.4, 5.4 and 1.6 nM , respectively) shares a high degree of structural similarity with a previously reported dual PI3K'mTOR inhibitor PKI402 (35, PI3K??, PI3K?? and mTOR, IC50 values of 1.4, 9.2 and 1.7 nM , respectively) with a triazolopyrimidine scaffold[2]. PKI-587 was extensively tested in tissue culture and xenografts cancer models. In tissue culture of MDA-MB361, PKI-587 completely inhibited Akt phosphorylation at 30 nM. Experiments in MDAMB361 xenografts showed complete inhibition of Akt phosphorylation for 36h by 25mg/kg of PKI-587 injected iv. Dose-response analysis showed maximal anti-tumor effects at 10 mg/kg. Inhibition of Akt phosphorylation and xenograft tumor growth was also observed in HCT116 colon carcinoma, H1975 (non-small cell lung cancer) and U87 (glioma) models [16].

In a recent letter, Aranapakam M et al. reported [24] the design and synthesis of several bis-morpholino triazine based compounds as potent dual PI3K/mTOR inhibitors. Replacement of one of the bis-morpholines in compound 34 (PKI-587) with 3-oxa-8-azabicyclo [3,2,1]octane and reduction of the molecular weight yielded compound 36 (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. 36 (PKI-179) is a potent dual PI3K/ mTOR inhibitor and exhibits excellent in vitro cell activity and in vivo efficacy in the MDA-361 xenograft model. Its effect on other tumor models is currently under investigation.

Christoph M. et al. reported [25]Compound 37 showed an in vitro profile superior to that of preclinical candidate 35 and comparable to clinical candidate 34. Furthermore, in vivo biomarker studies showed that compound 37 was more potent than compound 35, but not quite as potent as 34. More result from our ongoing optimization effort of 37 will be reported in due course.

In a U87 MG cellular assay measuring phosphorylation of Akt, compound 38 was reported by Ryan P et al. [26] ang displayed low double digit nanomolar IC50 and exhibited good oral bioavailability in rats (Foral = 63%). Compound 38 also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC50 = 193 nM (91 ng/mL).

3 Heat shock protein 90 (Hsp90) inhibitors
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays an important role in regulating many proteins involved in signaling pathway and cell proliferation[27-28]. Once identified in 1987 as one of the most abundant intracellular proteins, Hsp90 has received considerable attention and emerged as an attractive cancer therapeutic target due to its chaperoning function of the substrate proteins. In this regard, the inhibition of Hsp90's chaperoning function can induce simultaneous blockage of several signaling pathways in tumor cells so as to overcome the inevitable drug resistance of conventional cancer therapeutic agents[29].
In humans, Hsp90 has two cytosolic isoforms, Hsp90?? (inducible form) and Hsp90b (constitutive form), and the functional differences between these isoforms are poorly understood. Recent studies showed that cancer cells need secretion of Hsp90a into the extracellular matrix for invasion and metastasis [30]. Hsp90 exists predominantly as a homodimer in the cytoplasm and consists of three main domains, namely, the N-terminal, middle, and C-terminal domains. The N-terminal domain contains a binding site to adenosine triphosphate (ATP), which needs to be hydrolyzed for chaperone activity to occur. The middle domain, as well as having a key role in binding many client proteins to Hsp90, also modulates the ATP hydrolysis by interacting with the c-phosphate of the ATP that is bound in the N-terminal pocket[31]. The C-terminal domain, which contains an additional ATP-binding site, is responsible for the inherent dimerization of Hsp90.
A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described by Atsushi Suda et al. . Start from lead compound (39) CH5015765 and natural Hsp90 inhibitor geldanamycin (40) with Hsp90, and identified CH5138303 (compound 41) in ordor to optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors. This compound showed high binding affinity for N-terminal Hsp90a (Kd = 0.52 nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50 = 0.098 lM, NCI-N87 IC50 = 0.066 ??M) and also displayed high oral bioavailability in mice (F = 44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition = 136%).[32]

4 FAK inhibitors
Focal adhesion kinase (FAK) is an ubiquitous non-receptor tyrosine' protein kinase highly conserved and localized in focal adhesions, which is activated following binding of integrins to the extracellular matrix (ECM) or upon growth factor stimulation including that mediated by VEGF(Vascular endothelial growth factor). FAK has been involved in angiogenesis as an important modulator during development evidenced by the early embryonic lethality of mice engineered to harbor an endothelial specific deletion of FAK.[33] FAK plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition. Overexpression and/or increased activity of FAK is common in a wide variety of human cancers [34] .Therefore, FAK was recently proposed as a potential target in the development of anti-cancer drugs. Some FAK inhibitors have been successfully developed, which inhibited glioma, neuroblastoma and ovarian tumor growth in vivo. Their efficacy in tumor models may be a result of their ability to potently inhibit tumor growth and tumor-associated angiogenesis.
. A series of novel diarylamino-1,3,5-triazine derivatives as FAK inhibitors was reported by Pascal Dao et al. . These inhibitors at significantly low concentration show substantial deleterious effects on endothelial cell viability and the best of our inhibitors showed a similar potency on cell viability. Compound 42 showed significant decrease of autophosphorylation of FAK in HUVEC cells, suggesting that the compound could effectively block a key event of FAK signaling pathway in living cells [35].

6 Carbonic anhydrase hCA IX and hCA XII inhibitors
Carbonic anhydrases (CA) are ubiquitous metalloenzymes that catalyze a simple reaction, the conversion of CO2 to bicarbonate ion and a proton.[36] They are involved in various physiological and pathological processes, serving as an important target for designing drugs useful in diseases like epilepsy and cancer[37]. CA inhibitors (CAIs) are well established drugs as diuretics and antiglaucoma agents, but recent research has shown that several CA isozymes are drug targets for cancer and infective diseases [38], tumour-associated CAs are known as hCA IX and hCA XII. There are 11 active CA isozymes known in human (Hilvo et al., 2005), some of which act in cytosol (I, II, and III), others that are membrane-bound isozymes (IV, VII, IX, XII, and XIV), a mitochondrial isozyme (V), and one secreted salivary isozyme (VI) [39].
Indeed, the levels of hCA IX'the best studied tumour-associated CA at this moment'dramatically increase in response to hypoxia, a characteristic of many tumours, via a direct transcriptional activation of the CA9 gene by the hypoxia inducible factor HIF-1, being also proven that the expression of this protein in tumours is generally a sign of poor prognosis[40].Recently, we and Pastorekova and co-workers [41] showed that hCA IX is involved in the tumour acidification processes, providing H+ ions to the extracellular milieu by means of the CO2 hydrationreaction to bicarbonate and protons. The pH of tumours is in fact more acidic by 0.5'1.0 pH unit than that of the surrounding normal tissue,[40] and this acidic environment seems to play a very important role both in the growth, dissemination and propagation of tumour cells and in their nonresponsiveness to chemo- and radiotherapy. Vladimir Garaj and co-workers have also proved [42] that inhibition of hCA IX in transfected cells or in cultured tumour cells by means of potent CA IX inhibitors developed in our laboratory leads to a diminution of the acidifying effects in these cells, with restoration of a more physiologic pH. This constitutes the proof-of-concept that inhibition of the tumour-associated CAs (two such isozymes are known at this moment, hCA IX and hCA XII) [40] may lead to novel therapeutic approaches in the fight against hypoxic tumours, which are generally less responsive or nonresponsive to all the classical chemotherapeutic drugs or to radiotherapy.[41]
The sulfonamides incorporating triazinyl moieties previously reported [43] by Garaj, V et al. were among the most potent and selective hCA IX inhibitors obtained up to now.Considering the versatile chemistry of cyanuric chloride (2,4, 6-trichloro-1,3,5-triazine),[43]and its reactions with various nucleophiles such as amines, amino-sulfon amides, alcohols, phenols, etc, Vladimir Garaj and co-workers[42] have reported novel CA inhibitors containing triazinyl moieties (Scheme 1). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of tumour-associated hCA IX. The new compounds inhibited hCA IX with inhibition constants in the range of 1.0'640 nM.

A new series of triazinylsubstituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties were reported by Fabrizio Carta et al.[44] These compounds showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both mammalian, tumor-associated and pathogenic organisms??-class CAs. The tumor-associated isoform hCA IX was inhibited by compounds 56,57 with K??1s 8'1.0 nM. The inhibition of the second isoform associated to tumors, hCA XII, has not been investigated earlier with this family of derivatives. that similar to hCA IX, the lead 53 was a highly effective hCA XII inhibitor (K??1of 0.35 nM). As for hCA IX, in the case of the leads 54 and 55, all substitution patterns explored here led to more effective hCA XII inhibitors (K1s in the range of 2.6'9.3 nM for compounds, 58'62)

Sulfonamide and sulfamate CAIs were reported by Amrita K and co-workers [38] to show substantial anti-glaucoma as well as anti-tumour activity in vitro and in vivo, when targeting either CA II (for the antiglaucoma action) or CA IX/XII (for the antitumor activity). They reported earlier that incorporation of a 1,3,5-triazine moiety in 4-aminobenzene sulfonamide scaffold leads to compounds with enhanced efficacy and specificity against the transmembrane isoforms hCA IX and XII, over the cytosolic forms hCA I and II.[45] whereas the tumor associated isoforms were potently inhibited, with K1s in the range of 1.2-34.1 nM against hCA IX and of 2.1-33.9 against hCA XII, respectively. The transmembrane tumor associated isoform hCA IX was effectively inhibited by the synthesized compounds with K1s in the range of 1.2-34.1 nM. Compounds 63, 64-67 showed inhibition constants K1 ranging from 1.2 to 5.9 nM, which is better than standard drugs AZM and EZM. hCA XII was also potently inhibited by the new compounds reported here, with inhibition constants ranging from 2.1 to 33.9 nM. Most of the compounds, such as 63-67 showed a very good activity with KIs in the low nanomolar range, of 2.1-4.1 nM, comparable with AZM (K1 of 5.7 nM). The monosubstituted compounds showed better hCA IX/hCA XII inhibition activity compared to the disubstituted derivatives incorporating similar scaffolds.

7 Inhibitor of Enolase
Enolase is a component of the glycolysis pathway and a 'moonlighting' protein, with important roles in diverse cellular processes that are not related to its function in glycolysis. Cancer cells show increased dependence on glycolysis to produce ATP; a phenomenon known as the Warburg effect.[46]This metabolic alteration is a fundamental difference between cancer cells and normal cells, offering a therapeutic strategy to selectively kill cancer cells using glycolysis inhibitors. It has also been shown that glycolysis inhibitors induce cancer cell death more effectively in a hypoxic environment, which occurs within developing tumors.Small molecule 'ENOblock' was reported by Da-Woon Jung et al.[47], which is the first, nonsubstrate analogue that directly binds to enolase and inhibits its activity. ENOblock was isolated by small molecule screening in a cancer cell assay to detect cytotoxic agents that function in hypoxic conditions, which has previously been shown to induce drug resistance.Further analysis revealed that ENOblock can inhibit cancer cell metastasis in vivo.

8 EGFR inhibirors
8.1 inhibitors for EGFR
The epidermal growth factor receptor (EGFR), as an important mediator of cell proliferation and survival, always results in the enhanced proliferation and survival of cancer cells.[48] Thus, molecular- targeted inhibition of the regulated EGFR has become an attractive therapeutic strategy in cancer therapy, especially in lung cancer therapy. Since 1980s, the small molecular kinase inhibitors have emerged as promising strategies to inhibit EGFR.
Compound 69 could inhibit mutant EGFR enzyme with IC50 of 1.5 ??M (IC50 > 100??M for WT EGFR) and was considered as the most potent selective hit reported by Fang Bai et al.[49] . Compound 70 was observed with'dual-effective' inhibitory effect against EGFR and mutant EGFR-T790M/L858R, meanwhile, also exhibited antiproliferative activities against A549, A431 and NCI-H1975 cell lines. compound 70 showed the inhibitory activity with IC50 values of 10.5 ?? 0.9 ??M for the mutant EGFR-dependent cell line, 7.7 ?? 1.3 ??M for A549 cell line and 8.0 ?? 1.6??M for A431 cell line.

8.2 Inhibitors targeting Tie-2 Kinase
Receptor tyrosine kinases (RTK) represent a large family of membrane-bound enzymes responsible for a diverse range of biological processes, including relay of angiogenic signals from tumor-secreted growth factors. These proteins all consist of an extracellular ligand-binding domain, a transmembrane region, and an intracellular kinase domain (ATP binding). RTKs known to be involved in tumor angiogenesis are the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase family members.[50] Tie-2 is an endothelial cell specific receptor tyrosine kinase that is involved in angiogenic processes such as vessel branching, sprouting, remodeling, maturation, and stability. Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation [51]. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to assess the usefulness of direct inhibition of Tie-2 signaling as a cancer therapy (alone or in conjunction with inhibition of other angiogenic kinases), it would be desirable to have a selective small molecule Tie-2 inhibitor that is free of confounding activities against other kinases that play a role in tumor angiogenesis. In contrast to the plethora of small molecule inhibitors of KDR (VEGFR-2) in the literature,to the best of our knowledge, there are only two reports of small molecule Tie-2 inhibitors that are highly selective over KDR. The first reported example is 71, described by Abbott Laboratories in 2001 as a potent inhibitor of Tie-2 (>100-fold selective over KDR), possessing antiangiogenic properties in vivo [52a,b]. In 2005, GlaxoSmithKline reported 72 as a selective Tie-2 inhibitor (>140-fold selective over KDR) that also demonstrated potency in a matrigel model of angiogenesis [52c].

Brian L. Hodous et al. disclosed the design and optimization of a novel class of potent and selective pyridinyl pyrimidine and pyridinyl triazine Tie-2 inhibitors [51].Compound 73 demonstrated good pharmacokinetic properties when administered by iv and po routes. This compound was potent in a Tie-2 autophosphorylation cellular assay (IC50) 62 nM) and possessed >30-fold selectivity over all kinases screened in enzyme assays. It reduced the amount of phosphorylated Tie-2 by 94% with respect to basal at the 3 h time point in a mouse pharmacodynamic study (Ang-1-stimulated phosphorylated Tie- 2) when dosed orally at 100 mg/kg. The tremendous selectivity and adequate cellular potency and PK properties of 73 enable it to function as a tool to better understand the role Tie-2 plays in angiogenesis and tumor progression.

9 Target microtubules
Microtubules, formed by tubulin molecules, are essential components of the cytoskeleton in eukaryotic cells and are involved in many important cellular processes including mitosis. As components of the mitotic spindle, microtubules have emerged as a strategic target in anticancer therapy. Trisubstituted 1,3,5-triazine derivatives such as tubulyzine (74) were also designed with potent microtubule disassembly properties[53].

Depending on the molecular structure of tubulin poison ,it is able to act with different binding sites on tubulin: with the vinca, taxane, colchicine and tubulizine domains.Despite existence of the broad range of antimitotic agents, only few examples reached so far clinical and commercial success. The failure of the plurality of these molecules could be attributed to poor therapeutic indexes'the balance between efficiency and toxicity, perhaps related to pharmacokinetics, to the solubility problems, low affinity of therapeutic agents to tubulin molecules in vivo trials and other unrecognized factors. One way to improve some of these pharmacological parameters is to construct therapeutic molecules in accordance with the concept of multivalency. Clear inhibition was reported by Yulia B et al.[54], and the rate of assembly as well as the final amount of microtubules was lower in the presence of 75 than in the control experiment.Compound 75, contain, probably, the optimal spacer between the tubulin-binding units, as it manifest the best combination of antiproliferative and tubulin binding activity (IC50 = 0.687 ?? 0.013).

10 Potent Cyclin-Dependent Kinase Inhibitors
Cyclin-dependent kinases (CDKs) play a key role in regulating cell cycle machinery.This family of kinases requires association with a cyclin regulatory subunit for activity. Different CDK/cyclin pairs are active during each phase of the cell cycle.[55]To date, at least 9 CDKs and more than 12 different cyclin families have been identified. Critical CDKs/cyclins for core cell cycle function are CDK1/cyclin B, CDK2/cyclin A, CDK2/ cyclin E, CDK4/cyclin D, and CDK6/cyclin D.[56] In addition, CDK5 activity is highest in the brain and may play a role in neurogenesis and Alzheimer's pathology while CDK7, CDK8, and CDK9 have been implicated in the modulation of RNA elongation.[57]An increasing body of evidence indicates that uncontrolled CDK activity is a common feature related to proliferative diseases such as cancer, psoriasis, and restenosis.In a literature review, discovery and lead optimization efforts have provided many CDK inhibitors over the past decade.
Gee-Hong Kuo et al. [58] reported a new series of potent CDK inhibitors of [1,3,5] triazine-pyridine with CGP-60474(76) and compound 77. Among these ,compound 78 displayed high inhibitory potency at CDK1 (IC50 ) 0.021 ??M), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3??. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 78 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase.

11 Rad6B inhibitors
The highly-regulated ubiquitin-proteasome system, responsible for degradation of >80% of cellular proteins, has proven to be a popular target for the development of new anticancer agents in recent years.[59] A major function of the protein ubiquitination system serves to polyubiquitinate (tag with small proteins) cellular proteins destined for proteasomal degradation.[60] Three successive classes of enzymes of increasing structural and mechanistic class diversity mediate protein ubiquitination,namely E1,E2,E3. Inhibitors of E2 ubiquitin conjugating enzymes are less well studied than their E3 counterparts, despite their potential as cancer drug targets in a number of cases. For example, the E2 enzyme Rad6B has been found to be essential for post-replication DNA repair, and Rad6B over-expression is reported in breast cancer cell lines and tumours. Constitutive Rad6B over-expression in nontransformed cells is associated with induction of cancer phenotypic changes including centrosome amplification, abnormal mitosis and aneuploidy.[61] The ability of Rad6B to ubiquitinate ??-catenin leads to conjugates insensitive to proteasomal degradation. Consequent stabilisation and activation of oncogenic??-catenin provides further evidence of the therapeutic potential of Rad6B as a drug target, particularly in breast cancer.[62]
Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides have been reported by Hend Kothayer and co-workers[63], based on the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ8(79) and TZ9(80). These new triazine derivatives were tested for in vitro anticancer activity against the Rad6B expressing human breast cancer cell lines MDA-MB-231 and MCF-7. Active compounds, such as the triazinyl-carbohydrazides81'85, were found to exhibit low micromolar IC50 values particularly in the Rad6B-overexpressing MDA-MB-231 cell line, and triazine carboxamide 86 was the most active compound against MCF-7 cells. The molecular modelling studies and cell line activity profile are consistent with Rad6B as a potential mechanistic target underpinning in vitro anticancer activity.

13 ROCK1 inhibitors
Rho-associated protein kinases (ROCKs) are central and prominent downstream effectors of the Rho GTP-binding proteins that belong to Ras superfamily, which has been found to be mutated in about 30% of all human cancers.[64] ROCKs are involved in diverse cellular functions, smoothmuscle contraction, actin cytoskeleton organization, cell adhesion and motility, and gene expression.[65] The two ROCK isoforms, ROCK1 and ROCK2, share high sequence homology especially in the catalytic kinase domain (89%identity).ROCK1 is mainly expressed in lung, liver, spleen, kidney and testis, but ROCK2 is mostly expressed in brain and heart. Some potent ROCK inhibitors are currently in clinical trials. However, fasudil is the only ROCK inhibitor that has been approved for clinical use in Japan to prevent cerebral vasospasm after subarachnoid hemorrhage.[66] Therefore, the identification and design of new ROCK1 inhibitors for the development of new therapies is quite necessary.
Recently, Mingyun Shen reported [67] a new ROCK1 inhibitor with the triazine group by screening a small-scale compound library in our group. This inhibitor not only has obvious ROCK1 inhibition activity but also has good anti-proliferative activity against several cancer cell lines, suggesting that it is worthy of further study. The ROCK1 kinase inhibition assay illustrates that the IC50 of inhibitor 87 is 11.2 ??M, inhibitor 87 can inhibit the proliferation of lung cancer cells (A549 and H460) and myeloma cells (LP1 and OPM-2) effectively. The EC50 values of three cell lines (A549, LP1 and OPM-2) are lower than 10 ??M, and that of the H460 cell line is lower than 15 ??M. The remarkable potency of inhibitor 87 to kill A549 cancer cells (EC50 = 7.6 + 0.60??M) suggests that this inhibitor deserves more study.The IC50 of Compound 88 is 6 ??M and it is also a potent ROCK1 inhibitor.

This review presents the most recent advances in the development of various 1,3,5-triazine derivatives anticancer agents. More anticancer inhibitor need to be screened from different sources and their modes of action must be ascertained. Also, the efficiency of the existing molecules needs to be improved via biotransformation or synthetic routes.
References and notes
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