An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient

Requirement of Mucosa‐Associated Lymphoid Tissue Lymphoma Translocation Protein 1 Protease Activity for Fcγ Receptor–Induced Arthritis, but Not Fcγ Receptor–Mediated Platelet Elimination, in Mice

“…Using a previously reported low molecular weight inhibitor of Syk (Cpd11) , we efficiently abrogated IC‐driven cytokine release in both WT murine neutrophils (Figure C) and BMDCs (Figure D), substantiating the requirement of Syk enzymatic activity for FcγR‐induced proinflammatory cytokine release by murine myeloid cells. To extend the findings obtained with Malt1 PD mouse cells, we next evaluated the impact of a novel MALT‐1 protease inhibitor (MLT‐748) displaying similar potency and selectivity to the recently described inhibitor MLT‐827 (Supplementary Figure 1A, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.41204/abstract) . Consistent with the observations obtained using Malt1 PD mouse cells, treatment with 1 μ M MLT‐748 efficiently inhibited IC‐driven TNF, IL‐6, and keratinocyte chemoattractant/growth‐related oncogene production in WT mouse neutrophils (Figure C) and BMDCs (Figure D).…”

GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

“…These findings have led to considerable interest in the development of inhibitors of MALT1 protease activity as therapeutic agents. Multiple distinct categories of small-molecule MALT1 protease inhibitors have been reported, including (a) phenothiazine derivatives (e.g., mepazine), which bind to an allosteric site located between the MALT1 Ig3 domain and catalytic domain, and reversibly inhibit MALT1 by preventing the rearrangement of the enzyme into an active conformation (29); (b) MI-2 and its derivatives, which are irreversible inhibitors thought to covalently modify the MALT1 active site cysteine (27,71); (c) β-lapachone analogs, which are also irreversible inhibitors that form a covalent bond with the MALT1 catalytic cysteine (72); and (d) MLT-748 and MLT-747, which are closely related allosteric inhibitors that bind to the interface between the catalytic and Ig3 domains (73). Our current study suggests that GRK2 inhibits MALT1 proteolytic activity via a mechanism distinct from that of these MALT1 protease inhibitors, by interacting with the MALT1 DD.…”

Stabilizing Inactive Conformations of MALT1 as an Effective Approach to Inhibit Its Protease Activity

“…For clarity, only one MALT1 Casp‐Ig3 monomer is shown. Green spheres highlight the methionine Cε affected by binding of compound 1 and orange spheres the ones affected by compound 3 as well as other allosteric site binders such as previously published MLT‐748 [ 17 ] (see Figure S1e,f, Supporting Information).…”

“…Consequently, the catalytic center is disrupted and adopts a conformation that resembles the one observed for ligand‐free MALT1 [ 12a ] (Figure S2c, Supporting Information) and the ones observed for MALT1 in complex with allosteric inhibitors. [ 11g,17 ] Together, the NMR binding data and the cocrystal structure with compound 1 show that active site directed ligands can inhibit MALT1 by stabilization of an inactive conformation, by binding both to the monomer and the inactive dimer. These results are consistent with the previously published hypothesis [ 12a,18 ] suggesting that MALT1 can be activated in a two‐step process where dimerization is followed by a local restructuring of a catalytically incompetent dimer to the fully mature protease.…”

“…Also other ligands described for this pocket such as phenothiazine derivatives [ 11g ] and MLT‐748 [ 17 ] contain a lipophilic moiety as the main pharmacophore, which binds to the “W580 pocket” and superimposes well (Figure S3b, Supporting Information). However, mutation experiments showed that polar interactions with E397 were required for efficient binding of the phenothiazines and, to a lesser extent, of MLT‐748 .…”