1. Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors
- Author
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Sabita Thapa, Zhiqing Liu, John F. Hancock, Xiaoping Ma, Jeffrey A. Frost, Dharini van der Hoeven, Jia Zhou, Haiying Chen, Wei Chen, Na Ye, Dina Montufar-Solis, Ransome van der Hoeven, Kwang-Jin Cho, Pingyuan Wang, and Kristen M. Rehl
- Subjects
Drug ,media_common.quotation_subject ,Mice, Nude ,Antineoplastic Agents ,medicine.disease_cause ,01 natural sciences ,Malignant transformation ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Dogs ,Pancreatic cancer ,Drug Discovery ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Cells, Cultured ,030304 developmental biology ,media_common ,Cell Proliferation ,Pharmacology ,0303 health sciences ,Fendiline ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Cell growth ,Chemistry ,Organic Chemistry ,Cell Membrane ,General Medicine ,Neoplasms, Experimental ,medicine.disease ,0104 chemical sciences ,Membrane ,Cancer research ,Female ,KRAS ,Drug Screening Assays, Antitumor ,Function (biology) - 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.
- Published
- 2020