Related Experiment Video

Updated: Jun 18, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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
PubMed

Insights

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.
Keywords:
Cbl-bE3 ubiquitin ligasecancer immunotherapyin vivo efficacyinactive-state inhibitorspharmacokineticsstructure−activity relationship

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