2. Academic Validation
  3. Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors

  • J Med Chem. 2024 Jan 25;67(2):1500-1512. doi: 10.1021/acs.jmedchem.3c02083.
Adelphe M Mfuh 1,  Jeffrey A Boerth 1,  Gayathri Bommakanti 2,  Christina Chan 3,  Alex J Chinn 1,  Erin Code 2,  Patrick J Fricke 1,  Kathryn A Giblin 3,  Andrea Gohlke 4,  Catherine Hansel 4,  Niresh Hariparsad 1,  Samantha J Hughes 3,  Meizhong Jin 1,  Vasudev Kantae 4,  Stefan L Kavanagh 4,  Michelle L Lamb 1,  Jordan Lane 4,  Rachel Moore 4,  Taranee Puri 1,  Taylor R Quinn 1,  Iswarya Reddy 2,  Graeme R Robb 3,  Kevin J Robbins 1,  Miguel Gancedo Rodrigo 4 5,  Marianne Schimpl 3,  Baljinder Singh 1,  Meha Singh 1,  Haoran Tang 4,  Clare Thomson 3,  Jarrod J Walsh 4,  Jamie Ware 4,  Iain D G Watson 1,  Min-Wei Ye 2,  Gail L Wrigley 3,  Andrew X Zhang 2,  Yun Zhang 1,  Neil P Grimster 1
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 2 Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 3 Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 4 Discovery Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, U.K.
  • 5 Isomorphic Laboratories, 280 Bishopsgate, London EC2M 4RB, U.K.
PMID: 38227216 DOI: 10.1021/acs.jmedchem.3c02083
Abstract

Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b Ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

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