Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 547.2 Organic chemical reactions formerly 547.139

Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019

Mô tả vật lý: Size: p. 2154-2171 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 260088

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 thus 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.
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