2ydj | pdb_00002ydj

Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas

spinqualitylabelsall models 2ydj, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2ydj is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: CSS, PO4, YDJ 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 kinases, CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest allowing sufficient time for DNA repair. Agents which lead to abrogation of such checkpoints have potential to increase the efficacy of such as chemo- and radio-therapies. Thiophene carboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2, and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targetted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKbeta key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead, 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), that strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models. Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by Structure Based Design and Optimization of Thiophene Carboxamide Ureas.,Oza VB, Ashwell S, Almeida L, Brassil P, Breed J, Deng C, Gero T, Grondine M, Horn C, Ioannidis S, Liu D, Lyne PD, Newcombe N, Pass M, Read J, Ready S, Rowsell S, Su M, Toader D, Vasbinder M, Yu D, Yu Y, Xue Y, Zabludoff S, Janetka J J Med Chem. 2012 May 2. PMID:22551018 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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