Optimization and In Vivo Characterization of a Series of Cbl‑b Inactive-State Inhibitors.
Michael J Lambrecht1, Jun Liang1, Peter Man-Un Ung1
1Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
ACS Medicinal Chemistry Letters
|June 17, 2026
Summary
Researchers optimized Casitas B-lineage lymphoma-b (Cbl-b) inhibitors for cancer immunotherapy. Compound 16 showed good potency and properties, successfully inhibiting tumor growth in a mouse model.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Casitas B-lineage lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates immune responses.
- Inhibiting Cbl-b is a potential strategy for enhancing cancer immunotherapy.
- Optimizing Cbl-b inhibitors requires improving both potency and pharmacokinetic profiles.
Purpose of the Study:
- To optimize inactive-state Cbl-b inhibitors.
- To enhance inhibitor potency and pharmacokinetic properties.
- To evaluate the efficacy of optimized inhibitors in a preclinical cancer model.
Main Methods:
- Systematic chemical modification of benzylic amine and linker regions of Cbl-b inhibitors.
- Biochemical and cellular assays to assess inhibitor potency and activity.
- In vitro ADME profiling and in vivo pharmacokinetic studies.
- Evaluation of tumor growth inhibition in a murine CT26 colon-cancer model.
Main Results:
- Compound 16 was identified with an improved balance of biochemical potency, cellular activity, and in vitro ADME properties.
- Despite high in vivo IV clearance, compound 16 achieved sufficient oral exposure.
- Compound 16 demonstrated significant tumor growth inhibition in the CT26 colon-cancer model.
Conclusions:
- Optimized Cbl-b inhibitors, like compound 16, hold promise for cancer immunotherapy.
- Compound 16 exhibits favorable preclinical efficacy, warranting further investigation.
- Targeting Cbl-b with optimized inhibitors represents a viable therapeutic strategy for cancer treatment.
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