Friday, April 9, 2021

Discovery of a Potent and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase with Oral Anti-Inflammatory Activity

Mark S. Tichenor, John J. M. Wiener, Navin L. Rao, Charlotte Pooley Deckhut, J. Kent Barbay, Kevin D. Kreutter, Genesis M. Bacani, Jianmei Wei, Leon Chang, Heather E. Murrey, Weixue Wang, Kay Ahn, Michael Huber, Elizabeth Rex, Kevin J. Coe, JieJun Wu, Mark Seierstad, Scott D. Bembenek, Kristi A. Leonard, Alec D. Lebsack, Jennifer D. Venable, and James P. Edwards

ACS Medicinal Chemistry Letters 2021

DOI: 10.1021/acsmedchemlett.1c00044

Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...