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

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.