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 , which is a potent and orally bioavailable CBLB inhibitor with favorable ADME properties. In vivo studies demonstrated that compound 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.