127918-65-4Relevant academic research and scientific papers
Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies
Simpson, Graham L.,Bertrand, Sophie M.,Borthwick, Jennifer A.,Campobasso, Nino,Chabanet, Julien,Chen, Susan,Coggins, Julia,Cottom, Josh,Christensen, Siegfried B.,Dawson, Helen C.,Evans, Helen L.,Hobbs, Andrew N.,Hong, Xuan,Mangatt, Biju,Munoz-Muriedas, Jordi,Oliff, Allen,Qin, Donghui,Scott-Stevens, Paul,Ward, Paris,Washio, Yoshiaki,Yang, Jingsong,Young, Robert J.
, p. 2154 - 2171 (2019)
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.
