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.