Rational design of small molecule RHOA inhibitors for gastric cancer

Jin Hee Kim, Sungjin Park, Seung Mook Lim, Hyo Jin Eom, Curt Balch, Jinhyuk Lee, Gi Jin Kim, Jin Hyun Jeong, Seungyoon Nam, Yon Hui Kim

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)601-612
Number of pages12
JournalPharmacogenomics Journal
Volume20
Issue number4
DOIs
Publication statusPublished - 2020 Aug 1

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

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