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6NPE

C-abl Kinase domain with the activator(cmpd6), 2-cyano-N-(4-(3,4-dichlorophenyl)thiazol-2-yl)acetamide

Summary for 6NPE
Entry DOI10.2210/pdb6npe/pdb
DescriptorTyrosine-protein kinase ABL1, SULFATE ION, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, ... (6 entities in total)
Functional Keywordsactivator, kinase, allosteric, signaling protein, transferase
Biological sourceHomo sapiens (Human)
Total number of polymer chains2
Total formula weight71827.43
Authors
campobasso, N. (deposition date: 2019-01-17, release date: 2019-03-13, Last modification date: 2024-03-13)
Primary citationSimpson, G.L.,Bertrand, S.M.,Borthwick, J.A.,Campobasso, N.,Chabanet, J.,Chen, S.,Coggins, J.,Cottom, J.,Christensen, S.B.,Dawson, H.C.,Evans, H.L.,Hobbs, A.N.,Hong, X.,Mangatt, B.,Munoz-Muriedas, J.,Oliff, A.,Qin, D.,Scott-Stevens, P.,Ward, P.,Washio, Y.,Yang, J.,Young, R.J.
Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.
J. Med. Chem., 62:2154-2171, 2019
Cited by
PubMed Abstract: Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.
PubMed: 30689376
DOI: 10.1021/acs.jmedchem.8b01872
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.15 Å)
Structure validation

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