Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an Arg-specific protease that cleaves multiple substrates, playing a key role in T- and B-cell receptor signaling in lymphocytes. MALT1 protease activity is reported to mediate normal and disease-associated lymphocyte proliferation. Several studies indicate that MALT1 inhibition may ameliorate autoimmune diseases and MALT1 also may be a potential therapeutic target of ABC-DLBCL.<br/>We have identified a series of MALT1 inhibitors from a weak hit compound. The original hit, pyrazole amide inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search let to the discovery of benzensulfonylguanidine core that shows good potency and metabolic stability. Advanced compound shows good oral bioavailability and in vivo anti-psoriatic activity.

Identification of orally bioavailable allosteric inhibitors of MALT1 with <i>in vivo</i> anti-psoriatic activity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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Identification of orally bioavailable allosteric inhibitors of MALT1 with in vivo anti-psoriatic activity