Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease

Pharmacological Inhibition of MALT1 Protease Leads to a Progressive IPEX-Like Pathology

“…Combination with T cell depleting agents (25) or other immunomodulatory drugs dampening the dominant pathogenic cell subsets and pathways (e.g., IFNγ receptor signaling) might delay or prevent the development of the severe immune alterations observed upon long-term MALT1 protease inhibition but might also introduce the risk of excessive immunosuppression. Potential treatment of lymphomas with a MALT1 inhibitor has been contemplated based on numerous studies showing that MALT1 protease function is a key driver for proliferation of e.g., ABC-DLBCL lymphomas (10,11) and MALT1 protease inhibitors are now entering clinical trials for these indications (43). Overall, our work highlighted the risks and challenges of pursuing with a MALT1 inhibitor into the clinic, and strongly advocates for careful monitoring of patients, who may enter trials with an already impaired health status.…”

Optimization of the In Vivo Potency of Pyrazolopyrimidine MALT1 Protease Inhibitors by Reducing Metabolism and Increasing Potency in Whole Blood

“…On the one hand, protease-inactivated MALT1 knock-in mice display reduced regulatory T cell (Treg) numbers, which is thought to drive inflammation in multiple organs and autoimmunity seen in these animals. − The effect of MALT1 protease inhibition on reducing Treg numbers has, on the other hand, recently been suggested to potentiate efficacy of check-point immunotherapy in cancer. , Overall, the therapeutic potential of MALT1 protease inhibitors remains an open question and there is a need for suitable compounds to explore the in vivo efficacy and safety profile of MALT1 protease inhibition. Several classes of covalent − and noncovalent allosteric − MALT1 protease inhibitors have been used to probe the effects of pharmacological MALT1 inhibition. In particular, the covalent inhibitor MI-2 led to decreased tumor growth of ABC-DLBCL xenographs in vivo.…”

Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors

“…Lead 8 has single digit micromolar cellular activity and a promising secondary pharmacology profile. Additionally, since compound 8 has excellent in vivo rat PK in contrast to some published allo-steric MALT1 inhibitors [10,11], we believe that (1s,4s)-N,N 0 -diaryl cyclohexane-1,4-diamines are a promising lead series for further optimization.…”

“…We next investigated the SAR around the newly discovered 3-chloro [1,2,4]triazolo [4,3-b]pyridazine. Removing the chloro substituent (9) leads to a >100-fold loss in potency, whereas replacing the chloro by a bromo (10) or a thiomethyl group (11) results in only slightly reduced potency. Alkyl residues like methyl (12), cyclopropyl (13), or trifluoromethyl (14) as well as an amino substituent (15) all result in a significant loss of potency, highlighting the importance of the nature of this substituent for MALT1 potency.…”