Accelerated <i>In Silico</i> Discovery of <b>SGR-1505</b> : A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies
MALT1 is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-κB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin's B-cell lymphomas. By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and a chemistry-aware compound enumeration workflow, extensive sets of <i>de novo</i> design ideas were explored to quickly identify a novel hit series. Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, <b>SGR-1505</b>, with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple <i>in vivo</i> B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.
Authors
- Karen Akinsanya
- Robert Abel (ORCID: https://orcid.org/0000-0003-2945-3145)
- Robert Pelletier (ORCID: https://orcid.org/0000-0003-2112-1461)
- Michael Trzoss
- Xiaoming Xu (ORCID: https://orcid.org/0000-0003-1938-9346)
- Haifeng Tang (ORCID: https://orcid.org/0000-0002-5073-0680)
- Lynnie Trzoss
- Goran Krilov (ORCID: https://orcid.org/0009-0008-7665-5448)
- Andrew T. Placzek (ORCID: https://orcid.org/0000-0002-1816-0382)
- Peter J. Skrdla (ORCID: https://orcid.org/0000-0002-4114-5236)
- Karen H. Dingley
- Renchao Wang (ORCID: https://orcid.org/0000-0001-6496-1810)
- Netonia Marshall
- Morgan Lawrenz (ORCID: https://orcid.org/0000-0002-4798-6423)
- Jeffrey A. Bell (ORCID: https://orcid.org/0000-0002-8310-0183)
- Paul Devine
- Matt Liu (ORCID: https://orcid.org/0000-0002-8586-7337)
- Zhe Nie (ORCID: https://orcid.org/0009-0009-5125-8929)
- Roman Shimanovich (ORCID: https://orcid.org/0000-0001-6359-5986)
- Shulu Feng (ORCID: https://orcid.org/0009-0009-2056-2063)
- Wu Yin (ORCID: https://orcid.org/0000-0002-5041-0134)
- Min Ye (ORCID: https://orcid.org/0000-0003-1065-0034)
- Zhijian Liu (ORCID: https://orcid.org/0000-0003-1841-2671)
- Weidong G. Lai (ORCID: https://orcid.org/0000-0001-5793-4478)
Institutions
- Schrodinger (United States) (US)
- Pharmaron (United Kingdom) (GB)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01494
- Citations
- 5
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 5.23