Optimization and In Vivo Characterization of a Series of Cbl-b Inactive-State Inhibitors

ACS Medicinal Chemistry Letters 2026 Open access

Read full text
Authors: Michael J. Lambrecht, Jun Liang, Peter M.U. Ung, Malcolm P. Huestis, Bing-yan Zhu, Lisa M. Barton, Georgette M. Castanedo, Jason R. Zbieg, Robin Larouche‐Gauthier, Araz Jakalian, Jean‐Philippe Leclerc, Arun Yadav
+23 more Pouyan Haghshenas, Samuel Aubert‐Nicol, Hossein Ismaili, Liang Zhao, Mélissa Leblanc, Yi-Xiang Wang, Shouliang Wang, Qiuyue Wang, Thomas Garner (18630951), Sophia Tan, Madeleine Prangley, Fabio Broccatelli, Jodie Pang, Jeremy Murray, Christine Yu, Peter Hsu, Sascha Rutz, Satoko Kakiuchi-Kiyota, Isabel Ishizuka, Dennis Leung, Ponien Kou, Linda Bao, Xiaojing Wang
DOI: 10.1021/acsmedchemlett.6c00103
Cited by: 1
References: 18

Abstract

Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, is a key negative regulator of immune function, and its inhibition is a promising strategy for cancer immunotherapy. Here, we show the optimization of a series of inactive-state Cbl-b inhibitors to improve their potency and pharmacokinetic properties. Through systematic modification of a benzylic amine and a linker region, compound 16 was identified, which demonstrates a favorable balance of biochemical potency, cellular activity, and in vitro ADME properties. Despite exhibiting high IV clearance in vivo, compound 16 achieved oral exposures sufficient to demonstrate significant tumor growth inhibition in a murine CT26 colon-cancer model.

Fields of Study & Subjects

Melanoma and MAPK Pathways Peptidase Inhibition and Analysis HER2/EGFR in Cancer Research

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
6
Pages
1253–1257
Publication date
14 May 2026
Language
EN