Preclinical characterization of the potent and selective MALT1 inhibitor safimaltib in B-cell lymphoma models
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.
Authors
- Nigel E. Austin
- Jan Willem Thuring (ORCID: https://orcid.org/0000-0003-4154-1586)
- Tatiana Perova
- James P. Edwards (ORCID: https://orcid.org/0000-0001-6545-1193)
- Kathryn E. Packman (ORCID: https://orcid.org/0000-0002-2686-6481)
- Anthony Greway
- Ulrike Philippar (ORCID: https://orcid.org/0000-0002-9028-3782)
- Marjolein van Heerden (ORCID: https://orcid.org/0000-0002-0852-092X)
- Bas‐jan van der Leede
- Ari M. Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- Nele Vloemans
- Stan Gaj
- Yann Abraham (ORCID: https://orcid.org/0000-0001-5600-5896)
- Marcello Gaudiano
- Katarzyna Wnuk-Lipińska (ORCID: https://orcid.org/0000-0003-2680-6603)
- Emanuele Trella
- Jan Snoeys (ORCID: https://orcid.org/0000-0003-3420-424X)
- Kristof Kimpe
- Maxwell D. Cummings (ORCID: https://orcid.org/0000-0002-4646-3903)
- Ivo Cornelissen
- Frank Jacobs (ORCID: https://orcid.org/0000-0002-5977-3943)
- Mariette Bekkers
- Diede van den Biggelaar (ORCID: https://orcid.org/0000-0001-5449-450X)
- Onyi Irrechukwu (ORCID: https://orcid.org/0009-0008-5978-2621)
- Franck Morschhauser (ORCID: https://orcid.org/0000-0002-3714-9824)
- Bie M. P. Verbist
- Ricardo M. Attar (ORCID: https://orcid.org/0000-0002-6942-8019)
- Katie Amssoms
- Jacqueline Bussolari (ORCID: https://orcid.org/0009-0005-9705-0913)
- Jacqueline Kinyamu-Akunda (ORCID: https://orcid.org/0009-0007-2789-4445)
- Bart P. Medaer
- John F. Gerecitano (ORCID: https://orcid.org/0009-0001-0501-5688)
- Rui Xu (ORCID: https://orcid.org/0009-0001-4615-3956)
- Lorena Fontán (ORCID: https://orcid.org/0000-0002-1021-3654)
- Sriram Balasubramanian (ORCID: https://orcid.org/0000-0003-2018-2094)
- Peter J. Connolly
- Min Xia (ORCID: https://orcid.org/0000-0002-1093-5008)
- Nele Fourneau (ORCID: https://orcid.org/0009-0000-9329-0649)
- Yusri Ali Elsayed
- Irene Guimerans-Lorenzo
- Joanna Grant (ORCID: https://orcid.org/0000-0002-7902-1925)
- Weimei Sun (ORCID: https://orcid.org/0009-0002-3587-2063)
- Tongfei Wu (ORCID: https://orcid.org/0009-0001-9716-5885)
Institutions
- Johnson & Johnson (United States) (US)
- Janssen (Belgium) (BE)
- Johnson & Johnson (Canada) (CA)
- Janssen (United States) (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-11-09
- DOI
- https://doi.org/10.1158/2643-3230.bcd-26-0182
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00