2. Academic Validation
  3. Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors

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

  • Eur J Med Chem. 2021 May 5:217:113381. doi: 10.1016/j.ejmech.2021.113381.
Pingyuan Wang 1,  Dharini van der Hoeven 2,  Na Ye 1,  Haiying Chen 1,  Zhiqing Liu 1,  Xiaoping Ma 3,  Dina Montufar-Solis 3,  Kristen M Rehl 4,  Kwang-Jin Cho 4,  Sabita Thapa 2,  Wei Chen 3,  Ransome van der Hoeven 2,  Jeffrey A Frost 3,  John F Hancock 5,  Jia Zhou 6
Affiliations

Affiliations

  • 1 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
  • 2 Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA.
  • 3 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 4 Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, 45435, USA.
  • 5 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. Electronic address: john.f.hancock@uth.tmc.edu.
  • 6 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address: jizhou@utmb.edu.
PMID: 33756124 DOI: 10.1016/j.ejmech.2021.113381
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.

Keywords

Fendiline; KRAS; Pancreatic cancer; Plasma membrane localization; Scaffold repurposing.

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