Abstract 835: A potent and selective small molecule inhibitor of CD38

Abstract Background: CD38 is a multifunctional ectoenzyme involved in NAD metabolism and is highly expressed in various hematological malignancies, making it a critical therapeutic target in oncology. By depleting NAD and producing immunosuppressive metabolites such as adenosine, CD38 supports tumor growth and creates an immunosuppressive microenvironment. Compared to CD38 antibodies, small-molecule inhibitor offer advantages, including better tissue penetration, oral bioavailability, and cost-effectiveness. CD38 inhibition may restore NAD levels, reverse immunosuppression, and enhance antitumor immune responses, potentially synergizing with immune checkpoint inhibitors (ICIs), providing a promising strategy for cancer therapy. Methods and Materials: Accelerated by the "Right 6D+AI" platform, AI-based screening and multi-angle evaluation were conducted on over 5, 000 virtual molecules, yielding candidate molecule N066 with IC50 activity below 1 nM. To explore the therapeutic potential, oral administration of N066 in mice assessed dose-dependent effects on NAD+ elevation and ADPR reduction in tissues such as the spleen and liver. In syngeneic cancer models, CD38 protein expression was evaluated using immunohistochemistry (IHC) following ICI treatment. In mouse solid tumor models, N066 was administered as monotherapy or combined with ICIs. Results: The small-molecule inhibited intracellular CD38 activity in cultured human primary T cells, increasing intracellular NAD+ levels. In mice, oral administration of the inhibitor resulted in a dose-dependent increase in NAD+ levels and a decrease in ADPR levels in tissues such as the spleen and liver. In syngeneic cancer models, monotherapy with the N066 showed antitumor activity correlated with changes in NAD+ and ADPR levels. In B16-F10 tumor-bearing mice, combining N066 with anti-PD-L1 therapy enhanced antitumor activity. Conclusion: CD38 small-molecule inhibitors N066 demonstrates good antitumor activity, highlighting its therapeutic potential. Citation Format: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen. A potent and selective small molecule inhibitor of CD38 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 835.