Identification and optimization of novel small c-Abl kinase activators using fragment and HTS methodologies

DOI: 10.1021/acs.jmedchem.8b01872

Authors: Graham L. Simpson (GlaxoSmithKline R&D) , Sophie M. Bertrand (GlaxoSmithKline R&D) , Jennifer A. Borthwick (GlaxoSmithKline R&D) , Nino Campobasso (GlaxoSmithKline R&D) , Julien Chabanet (GlaxoSmithKline R&D) , Susan Chen (GlaxoSmithKline R&D) , Julia Coggins (GlaxoSmithKline R&D) , Josh Cottom (GlaxoSmithKline R&D) , Siegfried B. Christensen (GlaxoSmithKline R&D) , Helen C. Dawson (GlaxoSmithKline R&D) , Helen L. Evans (GlaxoSmithKline R&D) , Andrew N. Hobbs (GlaxoSmithKline R&D) , Xuan Hong (GlaxoSmithKline R&D) , Biju Mangatt (GlaxoSmithKline R&D) , Jordi Munoz-muriedas (GlaxoSmithKline R&D) , Allen Oliff (GlaxoSmithKline R&D) , Donghui Qin (GlaxoSmithKline R&D) , Paul Scott-stevens (GlaxoSmithKline R&D) , Paris Ward (GlaxoSmithKline R&D) , Yoshiaki Washio (GlaxoSmithKline R&D) , Jingsong Yang (GlaxoSmithKline R&D) , Robert J. Young (GlaxoSmithKline R&D)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 62 , PAGES 2154 - 2171

State: Published (Approved)
Published: January 2019

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.

Subject Areas: Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography