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Introduction: Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway is a clear driver of B-cell lymphomas, especially the aggressive activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of the classical NF-κB signaling pathway downstream of B-cell receptor and T-cell receptor. MALT1 possesses 2 functions: a scaffolding function to recruit NF-κB signaling proteins and a protease function to cleave and inactivate inhibitors of the NF-κB signaling pathway. Methods: Using a high-throughput screen followed by iterative structure-activity relationship (SAR) analyses, the MALT1 inhibitor JNJ-67856633 was identified. The lead compound was evaluated using biochemical, in vitro cellular and in vivo tumor efficacy and safety models. Results: JNJ-67856633 is a potent, selective, allosteric inhibitor of MALT1 protease activity as measured by biochemical assays or downstream cellular cytokine readouts (IL 6/10) or direct MALT1 substrate cleavage (RelB, BCL10). The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent Bruton's Tyrosine Kinase (BTK) inhibitors. Furthermore, combination effects were observed in CD79b cellular ABC-DLBCL models when JNJ-67856633 was combined with a BTK inhibitor. JNJ-67856633 leads to potent in vivo pharmacodynamic shutdown in CD79b- as well as CARD11-mutant ABC-DLBCL models as measured by serum IL10 or uncleaved BCL10 levels in tumors. JNJ-67856633 exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI Ly3 and OCI Ly10, and mutation selection patient derived DLBCL xenografts. To address the role of MALT1 inhibition in T cells, primary human T cells derived from normal healthy volunteers were treated with JNJ-67856633 in vitro. Dose dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation was observed upon treatment with JNJ-67856633 suggesting a potential immune modulatory role of MALT1 inhibition. Conclusions: Phase 1 clinical trials assessing the safety and efficacy of JNJ-67856633 initiated in 2019. JNJ-67856633 is a combination partner for BTK inhibitors and a promising treatment option for BTKi-resistant tumors, with demonstrated preclinical activity in CARD11 mutant tumors. In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM, and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocation, represent another attractive target for MALT1 inhibition. Citation Format: Ulrike Philippar, Tianbao Lu, Nele Vloemans, Mariette Bekkers, Luc Van Nuffel, Marcello Gaudiano, Katarzyna Wnuk-Lipinska, Bas-jan Van Der Leede, Katie Amssoms, Kristof Kimpe, Bart Medaer, Tony Greway, Yann Abraham, Max Cummings, Emanuele Trella, Greet Vanhoof, Weimei Sun, Jan Willem Thuring, Peter Connolly, Jan Linders, Haopeng Rui, Sriram Balasubramanian, Amy Johnson, John Gerecitano, Jenna Goldberg, James P. Edwards, Yusri Elsayed, Jennifer Smit, Jaqueline Bussolari, Jaqueline Bussolari, Ricardo Attar. Discovery of JNJ-67856633: A novel, first-in-class MALT1 protease inhibitor for the treatment of B cell lymphomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5690.