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
  • 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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