Development of Potent and Orally Bioavailable MALT1 Inhibitors for Sjogren’s Syndrome: Efficacy and Safety Assessment

Abstract MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein (1) plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Previous reports showed that potent MALT1 inhibitor 1 was dominated by very high clearance, which could be linked to amide cleavage. Herein, we report compound 22, a potent and orally bioavailable inhibitor of MALT1. It was found that introduction of a small methyl substituent could be used to alleviate amide cleavage while maintaining potency, which could be described as a “magic methyl effect.” Notably, compound 22 demonstrated excellent pharmacokinetic properties with low clearance and high AUCinf, resulting in in vivo potency (inhibition of germinal center formation) to treat Sjögren’s syndrome. However, considering that compound 22 also showed data suggestive of the serious safety risks previously reported by Novartis, we decided to discontinue further research.