Notably, agents such as safimaltib (JNJ-67856633) have shown manageable safety profiles and preliminary antitumor activity in early-phase trials for relapsed/refractory B-cell malignancies. However, MALT1-targeted therapy poses a dual challenge: although inhibiting oncogenic signaling and tumor cell proliferation, it also disrupts immunosuppressive Treg function, risking autoimmune toxicity by compromising the tumor microenvironment. This review systematically analyzes MALT1's oncogenic roles across cancers, clarifies inhibitor mechanisms, and evaluates translational challenges and strategic opportunities for precision oncology and combination immunotherapy.

P1, N=98, Recruiting, Schrödinger, Inc. | N=52 --> 98 | Trial completion date: Mar 2026 --> Nov 2027 | Trial primary completion date: Mar 2026 --> Nov 2027

Co-administration with posaconazole increased SGR-1505 exposure 3-fold...Asymptomatic, reversible indirect hyperbilirubinemia occurred, consistent with inhibition of UGT1A1. SGR-1505 was well-tolerated and exhibited favorable pharmacokinetic and pharmacodynamic properties, supporting further clinical development.

P1, N=150, Recruiting, AbbVie | Trial completion date: Jun 2027 --> Jul 2029 | Trial primary completion date: Jun 2027 --> Jul 2029

Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, SGR-1505, with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple in vivo B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.

P1, N=40, Recruiting, Aurigene Discovery Technologies Limited | Not yet recruiting --> Recruiting

P1, N=150, Recruiting, AbbVie | N=100 --> 150

P1, N=226, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

Mechanistically, telaprevir inhibited the recruitment of TRAF6 by MALT1, concomitant with the reduced recruitment of caspase-11 by TRAF6, and in turn, attenuated caspase-11 K63 poly-ubiquitination and activation, which was further confirmed by knockdown of TRAF6. Based on these results, we concluded that telaprevir could protect mouse heart against I/R injury by reducing caspase-11-dependent pyroptosis through inhibition of MALT1/TRAF6 pathway.

Provided herein are novel MALT1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

P1, N=50, Recruiting, Exscientia AI Limited

P1, N=45, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed