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Inhibitors of MALT1 for the Treatment of Lymphomas

Weill Cornell Medicine

Small molecule

Oncology

Hit To Lead or Lead Optimization

Technology Summary

Four lead compounds that inhibit MALT1 protease for the treatment of B cell lymphomas. Two have been tested in mouse models of diffuse large B-cell lymphoma (DLBCL). 

Background 

• Mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) is a critical mediator of B-Cell receptor signaling
• MALT1 mediates NF-κB signaling by functioning as a scaffold protein and protease to trigger downstream signals
• 70% of patients with activated B cell-like (ABC) DLBCL show a gain or amplification of MALT1
• The protease activity of MALT1 has been shown to be essential for the survival of ABC DLBCL cell lines that rely on constitutive NF-κB signaling 

 

Unmet Need

Selective MALT1 inhibitors as lead therapeutic candidates for ABC DLBCL

Technology Overview

The Melnick lab and its collaborators have developed four lead compounds from discovery campaigns. 

• One is a peptide-mimetic compound that irreversibly inhibits MALT1. It inhibits the growth of the OCI-Ly3 DLBL cancer cell line by decreasing proliferation and increasing apoptosis. It suppressed growth of DLBCL patient-derived xenografts ex vivo and was efficacious in vivo against DLBCL xenografted tumors in mice. It has a half-life of 4.3 hours in whole mouse blood. (D-7251)
• Another lead uses PROTAC chemistry, targeting both MALT1 and an E3 ubiquitin ligase, labeling MALT1 for degradation by the ubiquitin proteasome system. These have been tested in the OCI-Ly3 cell line. (D-7556)
• The third and fourth are allosteric inhibitors of MALT1, one a quinoline and the other a thiazolopyridine. Both are potent, with IC50 values of 10 nM and 13 nM, respectively. They have been tested on the OCI-Ly3 cell line and initial pharmacokinetics and pharmacodynamics have been evaluated in mice.

 

Ari M. Melnick

• US 9592223 B2 (2017.03.14)
Patent Family: KR, US, EP, JP, CN, CA, AU
• US 10711036 B2 (2020.07.14)
Patent Family: US, EP, JP
• US 10689366 B2 (2020.06.23)
Patent Family: US, EP, JP
• US 11248007 B2 (2022.02.15)
Patent Family: US, EP, JP

• "Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth". Fontan, L. et al. Journal of Clinical Investigation 2018, 128(10), 4397–4412
• "Quinoline and thiazolopyridine allosteric inhibitors of MALT1". Scott at al. Bioorganic & Medicinal Chemistry Letters 2019
• "Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth". Fontan at al. Journal of Clinical Investigation 2018

WCM_Poster_Inhibitors of MALT1 for the Treatment of Lymphomas.pdf
WCM_Slide deck_Inhibitors of MALT1 for the Treatment of Lymphomas.pdf
WCM_Patent_US 9592223 B2.pdf
WCM_Patent_US 10689366 B2.pdf
WCM_Pub_Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth.pdf