Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity
Jeffrey A. Boerth, Alex J. Chinn, Marianne Schimpl, Gayathri Bommakanti, Christina Chan, Erin Code, Kathryn A. Giblin, Andrea Gohlke, Catherine S. Hansel, Meizhong Jin, Stefan Kavanagh, Michelle L. Lamb, Jordan Lane, Carrie Larner, Adelphe M. Mfuh, Rachel 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
Abstract
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.