Conformation-tunable ATP-competitive kinase inhibitors. Issue 21 (23rd February 2022)

• Record Type: Journal Article
• Authors: Agius, Michael P.; Ko, Kristin; Johnson, Taylor K.; Phadke, Sameer; Soellner, Matthew B.
• Is Part Of: Chemical communications. Volume 58:Issue 21(2022)
• Page Start: 3541
• Page End: 3544
• Publication Date: 2022-02-23
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1039/d1cc06893h
• Languages: English
• ISSNs: 1359-7345

Abstract

Abstract : A library of conformation-selective inhibitors were synthesized and evaluated for their ability to impact kinase conformation. Abstract : Small molecule kinase inhibitors have shown immense clinical utility for diverse indications. While >60 kinase inhibitors have been approved (and many more in clinical trials), it remains unclear whether the clinical efficacy of a kinase inhibitor is solely dependent on enzymatic inhibition, or whether non-catalytic functions play a role in the efficacy of some kinase inhibitors. Here, we designed and synthesized a series of pyrazolopyrimidine kinase inhibitors that modulate the global kinase conformation of c-Src kinase. Expanding upon our findings from the pyrazolopyrimidine inhibitor series, we designed, synthesized, and evaluated three pair of conformation-selective kinase inhibitors, each with a unique hinge-binding scaffold. We profiled each pair of kinase inhibitors across 468 kinases and identified 38 kinases that could be studied using these pair of conformation-selective inhibitors. We also explore the binding of conformation-selective kinase inhibitors to mutant kinases of EGFR, FLT3, and KIT. Together, these studies yield important insight into the design of conformation-tunable kinase inhibitors and provide a toolset of compounds to study the role of protein conformation on kinase signaling.