Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which regulates activation, proliferation, and survival of T- and B- lymphocytes downstream of antigen recognition, is a key component in the canonical NF-kB signaling pathway. Stimulation of T- or B-cell receptors leads to recruitment of MALT1 into the CARMA1-BCL10-MALT1 (CBM) complex, in which it serves scaffolding and proteolytic roles. In its scaffolding role, MALT1 binds tumor necrosis factor receptor-associated factor (TRAF) and transforming growth factor-β-activated kinase 1 (TAK1), leading to activation of the Inhibitor kappa B (IkB) kinase complex and ultimately activation of the transcription factor NF-kB and cytokine secretion. MALT1 also contains a paracaspase (cysteine protease) domain, which, upon activation, cleaves a number of protein substrates that are part of a feedback loop controlling termination of the NF-kB response.<br/>MALT1 protease inhibitors have potential in oncology for the treatment of B-cell lymphomas driven by constitutive NF-kB activation. MALT1 protease function is required for optimal activation of T- and B- cells, suggesting potential utility in the treatment of immune-sensitive tumors. It has been demonstrated that MALT1 protease activity can be inhibited with small molecules acting at either the paracaspase active site or at an allosteric binding site. In this work we describe the discovery and optimization of a series of small molecule, allosteric inhibitors of the MALT1 protease that resulted in the discovery of JNJ-67856633. JNJ-67856633 potently inhibits MALT1 protease activity in biochemical and cellular assays as measured by downstream cytokine readouts (IL 6/10) or direct MALT1 substrate cleavage (RelB, BCL10). JNJ-67856633 exhibits potent tumor growth inhibition in human diffuse large B-cell lymphoma xenograft models, OCI Ly3 and OCI Ly10. JNJ-67856633 is currently in Phase 1 clinical studies as a single agent (NCT03900598) and in combination with a Bruton’s tyrosine kinase (BTK) inhibitor (NCT04657224).

Discovery of JNJ-67856633, a first-in-class allosteric MALT1 protease inhibitor for the treatment of cancer

ACS Spring Meeting 2021

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