1区 · 医学
Article
作者: Gohlke, Andrea ; Bommakanti, Gayathri ; Schimpl, Marianne ; Tang, Haoran ; Lamb, Michelle L. ; Chan, Christina ; Kantae, Vasudev ; Code, Erin ; Watson, Iain D. G. ; Mfuh, Adelphe M. ; Singh, Meha ; Giblin, Kathryn A. ; Puri, Taranee ; Robb, Graeme R. ; Wrigley, Gail L. ; Singh, Baljinder ; Boerth, Jeffrey A. ; Walsh, Jarrod J. ; Gancedo Rodrigo, Miguel ; Ye, Min-Wei ; Kavanagh, Stefan L. ; Moore, Rachel ; Thomson, Clare ; Robbins, Kevin J. ; Hariparsad, Niresh ; Ware, Jamie ; Zhang, Andrew X. ; Jin, Meizhong ; Zhang, Yun ; Reddy, Iswarya ; Hansel, Catherine ; Lane, Jordan ; Fricke, Patrick J. ; Quinn, Taylor R. ; Chinn, Alex J. ; Grimster, Neil P. ; Hughes, Samantha J.
Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.