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

Jun Liang¹, Michael J Lambrecht¹, Malcolm P Huestis¹

¹Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

ACS Medicinal Chemistry Letters

|June 17, 2026

Summary

Researchers developed a selective Cbl-b inhibitor (compound 33) that shows improved tumor growth inhibition and better tolerability compared to a previous pan-Cbl inhibitor (compound 6). This selective inhibitor offers a potential advantage in cancer therapy.

Keywords:

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

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Area of Science:

Medicinal Chemistry
Immunology
Pharmacology

Background:

Previous pan-Cbl inhibitor (compound 6) showed efficacy but lacked selectivity, leading to poor tolerability at higher doses.
Selectivity between Cbl-b and c-Cbl is crucial for improving therapeutic outcomes and reducing side effects.

Purpose of the Study:

To develop a Cbl-b selective inhibitor with improved efficacy and tolerability.
To investigate the therapeutic potential of selective Cbl-b inhibition in cancer models.

Main Methods:

Structure-activity relationship (SAR) optimization.
Surface plasmon resonance (SPR) for selectivity assessment.
In vivo efficacy studies in a CT26 syngeneic mouse model.
Pharmacokinetic profiling for oral exposure.

Main Results:

Achieved up to 37× Cbl-b selectivity, with lead compound 33 demonstrating 14× selectivity against c-Cbl by SPR.
Compound 33 showed potent activity in a PBMC cell assay and good oral bioavailability in mice.
Compound 33 exhibited superior tumor growth inhibition (TGI 145%) compared to compound 6 (TGI 82%) in the CT26 model.
Compound 33 was better tolerated than compound 6, supporting the hypothesis of selective Cbl-b inhibition advantage.

Conclusions:

A highly selective Cbl-b inhibitor (compound 33) was successfully developed.
Selective Cbl-b inhibition offers improved therapeutic index over pan-Cbl inhibition.
Compound 33 represents a promising candidate for further development in cancer treatment.