On December 7, 2020 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that preclinical data from its wholly-owned MALT1 inhibitor program in B-cell lymphomas at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Schrodinger, DEC 7, 2020, View Source [SID1234572362]). MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1, is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Schrödinger scientists have identified novel MALT1 inhibitors that have shown strong anti-tumor activity in preclinical models alone and in combination with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, and venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, two anti-cancer therapies used to treat certain B-cell lymphomas and CLL.
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"We are pleased our MALT1 inhibitors indicate promising preclinical anti-cancer activity in diffuse large B-cell lymphomas, commonly called DLBCL, as a single agent or in combinations. Our data suggest our lead molecules may expand therapeutic options for lymphoma patients who need alternative therapeutic options after relapse or becoming resistant to existing agents," said Karen Akinsanya, Ph.D., Executive Vice President, Chief Biomedical Scientist and Head of Discovery R&D at Schrödinger. "Our preclinical work is ongoing, and we plan to advance this program into IND-enabling studies in the first half of 2021."
The discovery of lead molecules in Schrödinger’s MALT1 program was accelerated with the company’s differentiated, physics-based platform, which facilitates exploration of vast amounts of chemical space. Schrödinger’s free energy perturbation technology (FEP+) was used in combination with machine learning to prioritize billions of computer- and human-designed compounds to identify and optimize potent, selective inhibitors with favorable drug-like properties in under one year.
Additional Details About the Study
The presentation, "Identification of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered by Schrödinger scientists. The company’s MALT1 compounds showed potent in vitro inhibition of MALT1 enzymatic activity, with high binding affinity to the protein. Strong in vivo anti-tumor activity was observed in mouse xenograft models of DLBCL. Additionally, strong in vivo anti-proliferative effects were reported in combination with ibrutinib and venetoclax in mouse models. Taken together, these data provide further rationale for developing MALT1 inhibitors as a potential therapeutic approach particularly in combination with existing therapies to potentially treat relapsed/refractory B-cell lymphoma and difficult to treat blood cancers such as DLBCL.