2yer

Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors

spinqualitylabelsall models 2yer, resolution 1.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2yer is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, SO4, TQ1 Related: 1ia8, 1nvq, 1nvr, 1nvs, 1zlt, 1zys, 2ayp, 2br1, 2brb, 2brg, 2brh, 2brm, 2brn, 2bro, 2c3j, 2c3k, 2c3l, 2cgu, 2cgv, 2cgw, 2cgx, 2wmq, 2wmr, 2wms, 2wmt, 2wmu, 2wmv, 2wmw, 2wmx, 2x8d, 2x8e, 2x8i, 2xey, 2xez, 2xf0, 2ydi, 2ydj, 2ydk, 2yex, 2ym3, 2ym4, 2ym5, 2ym6, 2ym7, 2ym8 Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CHK1_HUMAN] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition. Publication Abstract from PubMed Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e. Key challenges included modulation of physicochemical properties and pharmacokinetic (PK) parameters to enable compound testing in a Chk1 specific hollow fiber pharmacodynamic model. In this model, 16e was shown to abrogate topotecan-induced cell cycle arrest in a dose dependent manner. The demonstrated activity of TZs in this model in combination with a chemotherapeutic agent as well as radiotherapy validates this series of Chk1 inhibitors. X-ray crystal structures (PDB code: 2YEX and 2YER) for an initial lead and an optimized analog are also presented. Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors.,Oza V, Ashwell S, Brassil P, Breed J, Ezhuthachan J, Deng C, Grondine M, Horn C, Liu D, Lyne P, Newcombe N, Pass M, Read J, Su M, Toader D, Yu D, Yu Y, Zabludoff S Bioorg Med Chem Lett. 2012 Mar 15;22(6):2330-7. Epub 2012 Feb 1. PMID:22342147 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase

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