1. Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors.
- Author
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Wang P, van der Hoeven D, Ye N, Chen H, Liu Z, Ma X, Montufar-Solis D, Rehl KM, Cho KJ, Thapa S, Chen W, van der Hoeven R, Frost JA, Hancock JF, and Zhou J
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Membrane metabolism, Cell Proliferation drug effects, Cells, Cultured, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Female, Fendiline analogs & derivatives, Fendiline chemistry, Humans, Mice, Mice, Nude, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Proto-Oncogene Proteins p21(ras) metabolism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Cell Membrane drug effects, Enzyme Inhibitors pharmacology, Fendiline pharmacology, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors
- 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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