posted on 2024-01-16, 16:16authored byAdelphe M. Mfuh, Jeffrey A. Boerth, Gayathri Bommakanti, Christina Chan, Alex J. Chinn, Erin Code, Patrick J. Fricke, Kathryn A. Giblin, Andrea Gohlke, Catherine Hansel, Niresh Hariparsad, Samantha J. Hughes, Meizhong Jin, Vasudev Kantae, Stefan L. Kavanagh, Michelle L. Lamb, Jordan Lane, Rachel Moore, Taranee Puri, Taylor R. Quinn, Iswarya Reddy, Graeme R. Robb, Kevin J. Robbins, Miguel Gancedo Rodrigo, Marianne Schimpl, Baljinder Singh, Meha Singh, Haoran Tang, Clare Thomson, Jarrod J. Walsh, Jamie Ware, Iain D. G. Watson, Min-Wei Ye, Gail L. Wrigley, Andrew X. Zhang, Yun Zhang, Neil P. Grimster
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.