832P Characterisation of EXS73565: A potent and selective MALT1 inhibitor with low drug-drug interaction risk and potential in lymphoma

MALT1 plays a key role in antigen receptor signalling and preclinical data indicate that MALT1 protease inhibition may have benefit in tumours with dysregulated NF-κB signalling, including activated B-cell-diffuse large B-cell lymphoma (ABC-DLBCL). MALT1 inhibitors are in clinical development as monotherapies and in combination with other agnets for the treatment of oncology and haematology indications, including lymphoma. EXS73565 ('565) was designed using generative design, machine learning and molecular dynamics approaches. The compound was characterised in MALT1 protease assays and DLBCL functional studies. In vivo efficacy of '565 was assessed in mouse xenograft models, alone and in combination with the BTK inhibitor ibrutinib. Profiling of '565 was undertaken in a range of selectivity and preclinical studies. '565 is a potent and selective allosteric inhibitor of the MALT1 protease and inhibits the production of IL-10 and proliferation of DLBCL cells. In ABC-DLBCL xenograft studies, '565 demonstrated significant tumour growth inhibition. Tumour target engagement was demonstrated through measurement of the MALT1 protease target, RelB, and effects on NF-κB target genes. In an ABC-DLBCL xenograft model with low sensitivity to single-agent MALT1 and BTK inhibition in vivo, combining '565 and ibrutinib provided significant synergistic efficacy. Evaluation of '565 showed limited activity against CYP450 enzymes, hepatic and renal transporters. Notably, '565 avoids inhibition of UGT1A1 (an enzyme involved in metabolising bilirubin and certain small molecule drugs) in comparison to some clinical stage MALT1 inhibitors which carry a high UGT1A1 inhibition risk. We describe the characterisation of EXS73565, an allosteric inhibitor of MALT1 which is currently in IND/CTA-enabling studies. Importantly, we show that '565 exhibits a low drug-drug interaction and hyperbilirubinemia risk, offering the prospect of fully exploring the potential of MALT1 inhibition as a monotherapy and/or in combination with other targeted agents.