1569819-30-2Relevant academic research and scientific papers
Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors
Wang, Pingyuan,van der Hoeven, Dharini,Ye, Na,Chen, Haiying,Liu, Zhiqing,Ma, Xiaoping,Montufar-Solis, Dina,Rehl, Kristen M.,Cho, Kwang-Jin,Thapa, Sabita,Chen, Wei,van der Hoeven, Ransome,Frost, Jeffrey A.,Hancock, John F.,Zhou, Jia
, (2021/03/24)
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.
FENDILINE DERIVATIVES AND METHODS OF USE THEREOF
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Page/Page column 88, (2014/03/25)
Disclosed herein are novel derivatives of fendiline, including compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising these derivative compounds. Methods and intermediates useful for making the derivatives, and methods of using the derivatives, for example, for the inhibition of K-Ras plasma membrane localization, and compositions thereof, including for the treatment of cancer, are also provided.
