Abstract 3034: SY-12696, a novel and potent MALT1 protease inhibitor, for the treatment of B-cell lymphomas

Abstract Background: MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a key component of the CBM complex (CARD9/10/11/14-BCL10-MALT1) downstream of Bruton's tyrosine kinase (BTK) in the B-cell receptor signaling pathway. Through its unique scaffolding and proteolytic functions, MALT1 precisely modulates the NF-κB pathway and regulates cell proliferation, differentiation and immunity. MALT1 is major driver of a subset of B-cell lymphomas, making it an attractive target for therapeutic intervention. Inhibition of MALT1 is considered a promising therapeutic approach for the treatment of several B-cell lymphomas, including tumors with acquired BTK inhibitor (BTKi) resistance. Methods: Based on structure-activity relationship analysis, series of MALT1 inhibitors were synthesized and screened. The potency and downstream effects of compounds were evaluated using biochemical enzyme assay, cellular phenotype and functional studies and in vivo xenograft models. Furthermore, the potential for enhanced efficacy through combination with BTKi was investigated in TMD8 cells overexpressing the BTK C481S mutation. Results: SY-12696 was identified as a novel, potent and small molecular MALT1 inhibitor, it showed excellent potency on MALT1 protease activity both in biochemical and in cellular assays with nanomolar IC50s. SY-12696 suppressed cleavage of MALT1’s substrate (e.g. Rel B) in the activated B-cell subtype of diffuse large B cell lymphoma (ABC-DLBCL) cell lines, highlighting its capability to disrupt the NF-κB pathway. In cellular proliferation assays, SY-12696 effectively inhibited the growth of ABC-DLBCL cell lines, including the BTKi-resistant cell line OCI-Ly3 (carrying CARD11 L224P, MYD88 L265P mutations) and the BTKi-sensitive cell line OCI-Ly10 (carrying CD79A Δ191-208, MYD88 L265P mutations). In the OCI-Ly3 xenograft model, oral administration of SY-12696 at 10 mg/kg twice daily (bid) resulted in >90% tumor growth inhibition (TGI). Additionally, a synergistic effect of SY-12696 with the BTKi was observed on cell viability in TMD8-BTK C481S cells. The compound also exhibited desirable drug-like properties, including favorable pharmacokinetic properties and safety profile. Conclusion: Based on current studies, SY-12696 has demonstrated significant inhibitory potency on ABC-DLBCL cancer cells in vitro and in vivo, which makes SY-12696 a promising candidate for further development as a monotherapy or in combination with BTKi to treat relapsed/refractory B-cell lymphoma, particularly those resistance to BTKi. Citation Format: Xintao Cao, Jijun Li, Yongliang Sun, Chang Lu, Yuan Ji, Miao Zhang, Zhifeng Chen, Shenyu Zhao, Yan Zhu, Hong Luo, Yinghui Sun. SY-12696, a novel and potent MALT1 protease inhibitor, for the treatment of B-cell lymphomas [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 3034.