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, 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
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.