9FQJ

E3 ligase Cbl-b in complex with a carbamate scaffold inhibitor (compound 12)

This is a non-PDB format compatible entry.

Summary for 9FQJ

• Entry DOI: 10.2210/pdb9fqj/pdb
• Descriptor: E3 ubiquitin-protein ligase CBL-B, 2-cyclopropyl-6-methyl-~{N}-[3-[(6~{S})-6-methyl-2-oxidanylidene-1,3-oxazinan-6-yl]phenyl]pyrimidine-4-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 92659.47

Authors

Schimpl, M. (deposition date: 2024-06-17, release date: 2024-07-31, Last modification date: 2024-09-04)

Primary citation

Quinn, T.R.,Giblin, K.A.,Thomson, C.,Boerth, J.A.,Bommakanti, G.,Braybrooke, E.,Chan, C.,Chinn, A.J.,Code, E.,Cui, C.,Fan, Y.,Grimster, N.P.,Kohara, K.,Lamb, M.L.,Ma, L.,Mfuh, A.M.,Robb, G.R.,Robbins, K.J.,Schimpl, M.,Tang, H.,Ware, J.,Wrigley, G.L.,Xue, L.,Zhang, Y.,Zhu, H.,Hughes, S.J.
Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design.
J.Med.Chem., 67:14210-14233, 2024

PubMed Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the "Design" phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.

PubMed: 39132828
DOI: 10.1021/acs.jmedchem.4c01034

Experimental method

X-RAY DIFFRACTION (1.563 Å)