AI Developed ISM3830 a New CBLB Inhibitor

Insilico Medicine has nominated ISM3830, a potentially best-in-class oral CBLB inhibitor discovered through its proprietary Chemistry42 AI platform, as a preclinical candidate for advanced cancer immunotherapy.

This novel molecule targets Casitas B-lineage lymphoma-b (CBLB), an intracellular E3 ubiquitin ligase that acts as a master negative regulator of T-cell and natural killer (NK) cell activation, distinct from conventional surface checkpoint inhibitors like PD-1 or CTLA-4. By blocking CBLB, ISM3830 restores exhausted T-cell function, enhances anti-tumor immunity, and overcomes tumor-induced immunosuppression in preclinical models, demonstrating robust activity across multiple solid tumors with improved pharmacokinetics, oral bioavailability, and a favorable safety profile compared to prior candidates.​

The development of ISM3830 exemplifies AI-accelerated drug discovery, leveraging over 40 generative models within Chemistry42 for structure-based design guided by CBLB cocrystal structures, yielding a unique scaffold with only 0.42 similarity to existing molecules. Preclinical data show potent in vivo anti-tumor effects, long-term tumor immunity in rechallenge models, and synergy potential with checkpoint inhibitors, chemotherapies, and targeted agents, positioning it for IND-enabling studies and first-in-human trials in advanced solid tumors within 18-24 months. Published in the Journal of Medicinal Chemistry, the underlying series validation highlights iterative optimization for potency, selectivity, and druggability, addressing historical CBLB inhibitor challenges like metabolism and absorption.​

For prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC), ISM3830 holds substantial promise due to the disease’s “cold” tumor microenvironment characterized by low T-cell infiltration, minimal PD-L1 expression, and profound T-cell exhaustion marked by co-expression of PD-1, Tim-3, and other inhibitory receptors. Conventional PD-1 inhibitors yield objective response rates of just 3-5% in unselected mCRPC patients, underscoring the need for novel intracellular approaches.

Emerging clinical validation comes from NX-1607, another first-in-class CBLB inhibitor in Phase 1 trials, where 6 of 13 prostate cancer patients achieved ≥50% PSA reductions on optimized twice-daily dosing, including dramatic 90% drops with circulating tumor cell clearance in heavily pretreated cases. Translational data from SITC 2025 further confirmed NX-1607 increased CD8+ tumor-infiltrating lymphocytes in mCRPC, linking systemic immune activation to local microenvironment remodeling.

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