2. Academic Validation
  3. Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design

Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design

  • J Med Chem. 2024 Aug 22;67(16):14210-14233. doi: 10.1021/acs.jmedchem.4c01034.
Taylor R Quinn 1,  Kathryn A Giblin 2,  Clare Thomson 2,  Jeffrey A Boerth 1,  Gayathri Bommakanti 1,  Erin Braybrooke 2,  Christina Chan 2,  Alex J Chinn 1,  Erin Code 3,  Caifeng Cui 4,  Yukai Fan 4,  Neil P Grimster 1,  Keishi Kohara 2,  Michelle L Lamb 1,  Lina Ma 4,  Adelphe M Mfuh 1,  Graeme R Robb 2,  Kevin J Robbins 1,  Marianne Schimpl 5,  Haoran Tang 5,  Jamie Ware 5,  Gail L Wrigley 2,  Lin Xue 4,  Yun Zhang 1,  Huimin Zhu 4,  Samantha J Hughes 2
Affiliations

Affiliations

  • 1 Early TDE Discovery, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2 Early TDE Discovery, Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
  • 3 Discovery Sciences, R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 4 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
  • 5 Discovery Sciences, R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, U.K.
PMID: 39132828 DOI: 10.1021/acs.jmedchem.4c01034
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.

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