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Rational design of small molecule RHOA inhibitors for gastric cancer

Abstract

Previously, we identified Ras homologous A (RHOA) as a major signaling hub in gastric cancer (GC), the third most common cause of cancer death in the world, prompting us to rationally design an efficacious inhibitor of this oncogenic GTPase. Here, based on that previous work, we extend those computational analyses to further pharmacologically optimize anti-RHOA hydrazide derivatives for greater anti-GC potency. Two of these, JK-136 and JK-139, potently inhibited cell viability and migration/invasion of GC cell lines, and mouse xenografts, diversely expressing RHOA. Moreover, JK-136′s binding affinity for RHOA was >140-fold greater than Rhosin, a nonclinical RHOA inhibitor. Network analysis of JK-136/-139 vs. Rhosin treatments indicated downregulation of the sphingosine-1-phosphate, as an emerging cancer metabolic pathway in cell migration and motility. We assert that identifying and targeting oncogenic signaling hubs, such as RHOA, represents an emerging strategy for the design, characterization, and translation of new antineoplastics, against gastric and other cancers.

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Fig. 1: Novel inhibitors of RHOA.
Fig. 2: Small molecule RHOA inhibitors oppose cell growth and migration in GC.
Fig. 3: Binding pockets and potential binding interactions of the investigated molecules in the active site of RHOA (PDB code 4D0N).
Fig. 4: RHOA inhibitor inhibits activity of RHOA in GC cells.
Fig. 5: Network analysis of JK-136 and -139.
Fig. 6: RHOA inhibitor JK-136 and -139 inhibits tumor activities in animal models.

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Data availability

GSE135068 in Gene Expression Omnibus.

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Acknowledgements

This study was supported by grants from the National Research Foundation of Korea (MSIP) (2015R1A2A1A10052661 to YHK), and Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2016R1D1A1B03933145 to SN). The work was supported by the Gachon University Gil Medical Center (grant number FRD2019–11(2) to SN).

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Kim, JH., Park, S., Lim, S.M. et al. Rational design of small molecule RHOA inhibitors for gastric cancer. Pharmacogenomics J 20, 601–612 (2020). https://doi.org/10.1038/s41397-020-0153-6

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