Journal article
Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors
European journal of medicinal chemistry, Vol.217, pp.113381-113381
05/05/2021
DOI: 10.1016/j.ejmech.2021.113381
PMCID: PMC12933515
PMID: 33756124
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.
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•Scaffold repurposing and further structural modifications of fendiline are presented.•Several series of novel diversified analogs have been designed and synthesized.•12f, 12h and 22 are identified as potent and novel KRAS PM localization inhibitors.•In vitro, 12f, 12h and 22 inhibited oncogenic KRAS-driven cancer cell proliferation.•In vivo,12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth.
Details
- Title: Subtitle
- Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors
- Creators
- Pingyuan Wang - The University of Texas Medical Branch at GalvestonDharini van der Hoeven - The University of Texas Health Science Center at HoustonNa Ye - The University of Texas Medical Branch at GalvestonHaiying Chen - The University of Texas Medical Branch at GalvestonZhiqing Liu - The University of Texas Medical Branch at GalvestonXiaoping Ma - The University of Texas Health Science Center at HoustonDina Montufar-Solis - The University of Texas Health Science Center at HoustonKristen M. Rehl - Wright State UniversityKwang-Jin Cho - Wright State UniversitySabita Thapa - The University of Texas Health Science Center at HoustonWei Chen - The University of Texas Health Science Center at HoustonRansome van der Hoeven - The University of Texas Health Science Center at HoustonJeffrey A. Frost - The University of Texas Health Science Center at HoustonJohn F. Hancock - The University of Texas Health Science Center at HoustonJia Zhou - The University of Texas Medical Branch at Galveston
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.217, pp.113381-113381
- DOI
- 10.1016/j.ejmech.2021.113381
- PMID
- 33756124
- PMCID
- PMC12933515
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier Masson SAS
- Language
- English
- Date published
- 05/05/2021
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration; Dental Research; Periodontics
- Record Identifier
- 9984738106802771
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