Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies.

Autor:	Simpson GL; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Bertrand SM; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Borthwick JA; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Campobasso N; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Chabanet J; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Chen S, Coggins J; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Cottom J; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Christensen SB, Dawson HC; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Evans HL; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Hobbs AN; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Hong X; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Mangatt B; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Munoz-Muriedas J; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Oliff A; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Qin D; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Scott-Stevens P; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Ward P; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Washio Y; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K., Yang J; GlaxoSmithKline R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States., Young RJ; Medicines Research Centre , GlaxoSmithKline R&D , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Feb 28; Vol. 62 (4), pp. 2154-2171. Date of Electronic Publication: 2019 Feb 11.
DOI:	10.1021/acs.jmedchem.8b01872
Abstrakt:	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.
Databáze:	MEDLINE
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