Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors PMID: 31749904

ADC Targets in Oncology

2026-04-10

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors

ACS Med Chem Lett. 2019 Oct 11;10(11):1518-1523. doi: 10.1021/acsmedchemlett.9b00141.

Curt D Haffner ¹ , Adam K Charnley ¹ , Christopher J Aquino ¹ ² , Linda Casillas ¹ , Máire A Convery ² , Julie A Cox ¹ , Mark A Elban ¹ , Nicole C Goodwin ¹ , Peter J Gough ¹ , Pamela A Haile ¹ , Terry V Hughes ¹ ² , Beth Knapp-Reed ¹ , Constantine Kreatsoulas ¹ , Ami S Lakdawala ¹ , Huijie Li ¹ , Yiqian Lian ¹ , David Lipshutz ¹ , John F Mehlmann ¹ , Michael Ouellette ¹ , Joseph Romano ¹ , Lisa Shewchuk ¹ , Arthur Shu ¹ , Bartholomew J Votta ¹ , Huiqiang Zhou ¹ , John Bertin ¹ , Robert W Marquis ¹

Affiliations

Abstract

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.