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Small GTPases - Ras and Rho

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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Fragment-Based Discovery of a Small-Molecule RhoGDI2 Ligand, HR3119, that Inhibits Cancer Cell Migration.

Mingqing Liu¹, Shizhang Wan², Shuangxi Guo²

¹The First Affiliated Hospital and School of Life Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles and Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.

ACS Chemical Biology

|October 16, 2025

Summary

Researchers discovered HR3119, the first small molecule targeting RhoGDI2, a protein involved in cancer. This compound disrupts RhoGDI2-Rac1 binding and inhibits aggressive breast cancer cell migration, offering new drug discovery perspectives.

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Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

Guanine nucleotide dissociation inhibitors (GDIs), such as RhoGDI2, regulate Ras superfamily proteins, which are key cancer drug targets.
Directly targeting Ras proteins is challenging, making GDIs like RhoGDI2 attractive alternative targets for cancer therapy.
Previous efforts to target GDIs have yielded limited success, highlighting the need for novel approaches.

Purpose of the Study:

To discover and characterize the first small-molecule ligand for RhoGDI2.
To investigate the mechanism by which small molecules can disrupt RhoGDI2-protein interactions.
To evaluate the therapeutic potential of RhoGDI2 inhibitors in aggressive breast cancer models.

Main Methods:

Fragment-based drug discovery was employed, starting with a millimolar affinity hit.
Structure-based drug design, guided by crystal structures of ligand-bound RhoGDI2, was used to optimize the lead compound.
Biochemical assays were used to determine binding affinities (Kd) and assess the disruption of protein-protein interactions.
Cell-based assays were utilized to evaluate the compound's effects on cancer cell migration.

Main Results:

HR3119 was identified as the first RhoGDI2 ligand with low-micromolar affinity (Kd = 8 μM).
HR3119 was rationally designed to occupy the RhoGDI2-Rac1 protein-protein interaction interface, effectively disrupting their binding.
The (6R)-enantiomer of HR3119 showed significantly higher binding affinity (nearly 100-fold) compared to the (6S)-enantiomer.
(6R)-HR3119 engaged RhoGDI2 in cells and suppressed the migration of aggressive breast cancer cells.

Conclusions:

HR3119 represents a novel, first-in-class small molecule targeting RhoGDI2.
The study demonstrates a successful strategy for discovering RhoGDI2 inhibitors through structure-based design.
Targeting RhoGDI2 with compounds like (6R)-HR3119 shows promise for developing new therapies against aggressive breast cancer.