9MKC

Crystal structure of MALT1 in complex with an allosteric inhibitor

This is a non-PDB format compatible entry.

Summary for 9MKC

• Entry DOI: 10.2210/pdb9mkc/pdb
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, CALCIUM ION, N-[(8R)-2-chloro-7-(propan-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl]-N'-[5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]urea (3 entities in total)
• Functional Keywords: allosteric inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 88729.74

Authors

Bell, J.A. (deposition date: 2024-12-17, release date: 2025-10-29)

Primary citation

Nie, Z.,Trzoss, M.,Placzek, A.T.,Trzoss, L.,Krilov, G.,Feng, S.,Lawrenz, M.,Ye, M.,Marshall, N.,Dingley, K.H.,Pelletier, R.D.,Lai, W.G.,Bell, J.A.,Tang, H.,Devine, P.,Liu, Z.,Skrdla, P.,Shimanovich, R.,Liu, M.,Wang, R.,Xu, X.,Abel, R.,Akinsanya, K.,Yin, W.
Accelerated In Silico Discovery of SGR-1505 : A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies.
J.Med.Chem., 2025

PubMed Abstract: 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 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, , with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.

PubMed: 41078320
DOI: 10.1021/acs.jmedchem.5c01494

Experimental method

X-RAY DIFFRACTION (2.8 Å)