Preclinical characterization of the potent and selective MALT1 inhibitor safimaltib in B-cell lymphoma models

Constitutive activation of the B-cell receptor (BCR) pathway drives non-Hodgkin lymphomas. MALT1 is a key mediator of NF-κB signaling downstream of B- and T-cell receptors. Herein, we report development of safimaltib (JNJ-67856633), a selective, allosteric inhibitor of MALT1 protease. The crystal structure of safimaltib bound to MALT1 was determined, and enzyme kinetic studies were performed to characterize its inhibitory mechanism. Sub-micromolar doses of safimaltib inhibited growth of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines with activation of NF-κB signaling and models mimicking BTK inhibition resistance. Notably, activating mutations in BCR-pathway components were strongly associated with safimaltib response in vitro. Safimaltib demonstrated efficacy in DLBCL and MCL mouse models and synergy with a BTK inhibitor. Safimaltib was well tolerated in preclinical immunocompetent animal models with a safety profile supporting MALT1 targeting in humans. Overall, these results provide rationale for the first-in-human MALT1 inhibitor clinical trial.