posted on 2023-11-17, 19:37authored byJeffrey A. Boerth, Alex J. Chinn, Marianne Schimpl, Gayathri Bommakanti, Christina Chan, Erin L. Code, Kathryn A. Giblin, Andrea Gohlke, Catherine S. Hansel, Meizhong Jin, Stefan L. Kavanagh, Michelle L. Lamb, Jordan S. Lane, Carrie J. B. Larner, Adelphe M. Mfuh, Rachel K. Moore, Taranee Puri, Taylor R. Quinn, Minwei Ye, Kevin J. Robbins, Miguel Gancedo-Rodrigo, Haoran Tang, Jarrod Walsh, Jamie Ware, Gail L. Wrigley, Iswarya Karapa Reddy, Yun Zhang, Neil P. Grimster
Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is
a RING finger
E3 ligase that is responsible for repressing T-cell, natural killer
(NK) cell, and B-cell activation. The robust antitumor activity observed
in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity
justified our discovery effort toward Cbl-b inhibitors that might
show therapeutic promise in immuno-oncology, where activation of the
immune system can drive the recognition and killing of cancer cells.
We undertook a high-throughput screening campaign followed by structure-enabled
optimization to develop a novel benzodiazepine series of potent Cbl-b
inhibitors. This series displayed nanomolar levels of biochemical
potency, as well as potent T-cell activation. The functional activity
of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based
cellular assays.