Discovery and Biological Evaluation of Novel, Potent, and Orally Available CBLB Inhibitors

Casitas B-lineage lymphoma-b (CBLB) has emerged as a promising therapeutic target for cancer immunotherapy due to its central role in modulating T-cell activation and immune tolerance. In this work, we employed a structure-guided drug discovery approach, leveraging the cocrystal structure of CBLB with the hit compound to systematically optimize potency, selectivity, and pharmacokinetic profiles. Through iterative structure–activity relationship (SAR) exploration, we identified compound 10, which is a potent and orally bioavailable CBLB inhibitor with favorable ADME properties. In vivo studies demonstrated that compound 10 exhibits significant antitumor efficacy in syngeneic mouse models, synergizes strongly with anti-PD-1 therapy to enhance tumor regression, and induces durable immune memory against tumor rechallenge. Comprehensive PK/PD analyses revealed sustained target engagement and dose-dependent modulation of downstream biomarkers. Our detailed SAR elucidation provides a roadmap for further optimization of CBLB inhibitors.