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Direct Small Molecule Modulation of LILRB4 (ILT3) Restores Antitumor Immunity In Vivo and in Patient-Derived Cells
Somaya A Abdel-Rahman1, Zamara Mariam2, Giuseppe Deganutti2
1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
ACS Chemical Biology
|July 27, 2026
Summary
Researchers discovered GL-4512, a small molecule that targets the LILRB4 immune checkpoint. This drug disrupts tumor immune evasion and restores anti-cancer activity, offering a new non-biologic therapy for cancer immunotherapy.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Targeting myeloid immune checkpoints is crucial for cancer immunotherapy.
- Leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3) is an immunosuppressive checkpoint involved in tumor immune evasion and therapy resistance.
Purpose of the Study:
- To discover and characterize a small molecule modulator of LILRB4.
- To evaluate the therapeutic potential of LILRB4 inhibition in cancer models.
Main Methods:
- Dianthus-based TRIC screening identified GL-4512.
- Orthogonal biophysical studies (microscale thermophoresis, SPR, CETSA) confirmed target engagement.
- Molecular dynamics simulations and mutagenesis identified a novel binding pocket.
- Functional assays assessed signaling pathway disruption and immune cell activity.
- In vitro and in vivo cancer models (colorectal cancer, AML, CT26 tumors) were used for efficacy studies.
Main Results:
- GL-4512 directly binds LILRB4 with nanomolar affinity.
- The molecule disrupts the LILRB4-SCG2 axis and downstream signaling (SHP1/2, STAT3).
- LILRB4 inhibition restored anti-tumor immunity, enhanced T-cell activation, and reduced tumor cell viability in patient-derived models.
- GL-4512 demonstrated favorable pharmacokinetics and safety for oral administration.
- Oral GL-4512 suppressed tumor growth and enhanced immune activation in syngeneic colorectal tumors.
Conclusions:
- LILRB4 is a druggable target for direct small molecule immunomodulation.
- GL-4512 represents a promising non-biologic therapeutic strategy for targeting suppressive myeloid immune checkpoints in cancer.
