Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors

Pingyuan Wang, Dharini van der Hoeven, Na Ye, Haiying Chen, Zhiqing Liu, Xiaoping Ma, Dina Montufar-Solis, Kristen M. Rehl, Kwang Jin Cho, Sabita Thapa, Wei Chen, Ransome van der Hoeven, Jeffrey A. Frost, John F. Hancock, Jia Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1–5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.

Original languageEnglish (US)
Article number113381
JournalEuropean journal of medicinal chemistry
Volume217
DOIs
StatePublished - May 5 2021

Keywords

  • Fendiline
  • KRAS
  • Pancreatic cancer
  • Plasma membrane localization
  • Scaffold repurposing

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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