Optimization Leading to a Potent and Selective Cbl‑b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy PMID: 42305193

Target-related Cytokines

2026-09-23

Optimization Leading to a Potent and Selective Cbl‑b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy

ACS Med Chem Lett. 2026 May 27;17(6):1258-1265. doi: 10.1021/acsmedchemlett.6c00104.

Jun Liang ¹ , Michael J Lambrecht ¹ , Malcolm P Huestis ¹ , Bingyan Zhu ¹ , Lisa M Barton ¹ , Georgette M Castanedo ¹ , Peter Man-Un Ung ¹ , Robin Larouche-Gauthier ² , Araz Jakalian ² , Jean-Philippe Leclerc ² , Arun Yadav ² , Pouyan Haghshenas ² , Samuel Aubert-Nicol ² , Hossein Ismaili ² , Liang Zhao ² , Melissa Leblanc ² , Hugo de Almeida ² , Qiuyue Wang ³ , Thomas Garner ¹ , Sophia Tan ¹ , Madeleine S Prangley ¹ , Jodie Pang ¹ , Jeremy M Murray ¹ , Christine Yu ¹ , Peter L Hsu ¹ , Sascha Rutz ¹ , Isabel Ishizuka ¹ , Haochu Huang ¹ , Chan Gao ¹ , Min Chen ¹ , Liz Mutter-Rottmayer ¹ , Satoko Kakiuchi-Kiyota ¹ , Dennis H Leung ¹ , Ponien Kou ¹ , Linda Bao ¹ , Xiaojing Wang ¹

Affiliations

Abstract

In the preceding work in this issue (10.1021/acsmedchemlett.6c00103), we described our initial structure-activity relationship (SAR) optimization that led to a pan-Cbl inhibitor (6) that demonstrated efficacy in a mouse CT26 syngeneic model. Unfortunately, attempts to improve TGI with higher doses of 6 resulted in poor tolerability which we attributed to a lack of selectivity between Cbl-b and c-Cbl (∼2× by surface plasmon resonance (SPR)). Herein, we report our continued efforts that led to a breakthrough in achieving Cbl-b selectivity (up to 37×). The lead compound 33 demonstrated 14× selectivity against c-Cbl by SPR, was potent in a PBMC cell assay, and showed good oral exposure in mice. When tested in a CT26 model, 33 displayed improved tumor growth inhibition compared to our previously reported pan-Cbl inhibitor 6 (TGI 145% vs 82%). More importantly, 33 was better tolerated than 6, supporting our hypothesis that a selective Cbl-b inhibitor could be advantageous relative to a pan-Cbl inhibitor.

Keywords

Cancer Immunotherapy; Cbl-b; Druggability; Protein−Protein Interaction; RING E3 Ligase; Selectivity; Structure-Based Design.