MLT-747, an Allosteric MALT1 Inhibitor for Immunodeficiency Research

Immunodeficiency is a state, in which the immune system’s ability is absent. It is not able to fight against cancer or infectious diseases. MALT1 is the human paracaspase, with the full name of mucosa-associated lymphoid tissue lymphoma translocation protein 1. It plays a central role in the activation of T, B lymphocytes and NF-κB. In some immunodeficient patients lacking MALT1, the T cell and B cell receptor signaling is compromised. Researchers characterize a compound MLT-747 as the inhibitor of MALT1.

Jean Quancard, et al., carries out a series of experiments to find out the potency of MLT-747.

In the beginning, they explore the action of MLT-747 on MALT1. MLT-747 binds at the interface between the caspase and immunoglobulin (Ig3) domains. It takes place of Trp580 and locks the catalytic site in an inactive state. MLT-747 is a selective and allosteric MALT1 inhibitor, exhibits high affinity at MALT1, with an IC50 of 14 nM.

Then, researchers make a hypothesis that MLT-747 stabilizes the mutant MALT1-W580S protein. To prove this, they detect the activity of MLT-747 on MALT1-W580S. In patient (mut/mut) B cells, MLT-747 indeed binds and stabilizes MALT1-W580S, with an EC50 of 314 nM. After 24 hours, it increases MALT1-W580S protein levels in the MALT1 mutant cells. However, MLT-747 shows no obvious effect on MALT1-independent phosphorylation of ERK1 or ERK2.

In a word, MLT-747 is a potent, selective, allosteric inhibitor of MALT1. It binds MALT1 in the allosteric Trp580 pocket, with an IC50 of 14 nM. Further study needs to be done to prove more potency of MLT-747 in immunodeficient disease.

1. Quancard J, et al. Nat Chem Biol. 2019 Mar;15(3):304-313.