Preclinical characterization of the potent and selective MALT1 inhibitor safimaltib in B-cell lymphoma models
Year: 2026
Type: article
Abstract: Constitutive activation of the B-cell receptor (BCR) pathway drives non-Hodgkin lymphomas. MALT1 is a key mediator of NF-κB signaling downstream of B- and T-cell receptors. Herein, we report development of safimaltib (JNJ-67856633), a selective, allosteric inhibitor of MALT1 protease. The crystal structure of safimaltib bound to MALT1 was determined, and enzyme kinetic studies were performed to characterize its inhibitory mechanism. Sub-micromolar doses of safimaltib inhibited growth of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines with activation of NF-κB signaling and models mimicking BTK inhibition resistance. Notably, activating mutations in BCR-pathway components were strongly associated with safimaltib response in vitro. Safimaltib demonstrated efficacy in DLBCL and MCL mouse models and synergy with a BTK inhibitor. Safimaltib was well tolerated in preclinical immunocompetent animal models with a safety profile supporting MALT1 targeting in humans. Overall, these results provide rationale for the first-in-human MALT1 inhibitor clinical trial.
Source: Blood Cancer Discovery
Authors: Ulrike Philippar, Lorena Fontan, Min Xia, Nele Vloemans, Mariette Bekkers, Marcello Gaudiano, Onyi Irrechukwu, Diede van den Biggelaar, Tatiana Perova, Irene Guimerans-Lorenzo, Katarzyna Wnuk-Lipinska, Ivo Cornelissen, Marjolein van Heerden, Bas-Jan van der Leede, Katie Amssoms, Rui Xu, Joanna Grant, Emanuele Trella, Yann Abraham, Kristof Kimpe, Bart Medaer, Anthony Greway, Jan Snoeys, Frank Jacobs, Maxwell D. Cummings, Weimei Sun, Jan Willem. Thuring, Tongfei Wu, Stan Gaj, Bie Verbist, Peter J. Connolly, Nigel Austin, Sriram Balasubramanian, Jacqueline Kinyamu-Akunda, Kathryn Packman, James P. Edwards, Yusri Elsayed, Nele Fourneau, Franck Morschhauser, John F. Gerecitano, Jacqueline Bussolari, Ari M. Melnick, Ricardo M. Attar
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7225619315
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