Casitas B-lineage lymphoma b (CBL-B) is an E3 ubiquitin ligase expressed in immune cells that functions as a negative regulator of T cell, NK cell and myeloid cell signaling pathways. Mice deficient in cbl-b display anti-tumor activity in multiple syngeneic models, suggesting that inhibition of CBL-B may be a novel therapeutic strategy. Screening campaigns utilizing HTS, DEL and fragment libraries led to the discovery of several series of small-molecules that bind to CBL-B, and some of these were observed to glue the protein into an inactive conformation resulting in ligase inhibition. We present structure and property optimization supported by X-ray crystallography resulting in identification of a compound (NRX-8) with an KD = 20 nM. NRX-8 increases T cell activation in response to TCR stimulation at low nanomolar concentrations. NRX-8 inhibits tumor growth in syngeneic mouse models of cancer when dosed orally. Furthermore, we present preclinical data on NX-1607, a more potent CBL-B inhibitor currently being evaluated in a phase I trial in multiple oncology indications. Oral administration of NX-1607 in mice demonstrated significant single agent tumor growth inhibition and importantly, the combination of NX-1607 and anti-PD-1 can substantially increase the median overall survival and the frequency of complete tumor rejections in multiple tumor models.

Discovery and optimization of CBL-B inhibitors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.