ArticleEuropean journal of medicinal chemistry2021
Scaffold repurposing of fendiline: Identification of potent KRAS plasma membrane localization inhibitors.
Article in European journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.Acta pharmaceutica Sinica. B · 2025Article
- RAS(ON) Therapies on the Horizon to Address KRAS Resistance: Highlight on a Phase III Clinical Candidate Daraxonrasib (RMC-6236).Journal of medicinal chemistry · 2025Article
- KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways.Cells · 2024Review
- Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS.Signal transduction and targeted therapy · 2023Review
- Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding.EMBO reports · 2022Article
- Mechanisms of phosphatidylserine influence on viral production: A computational model of Ebola virus matrix protein assembly.The Journal of biological chemistry · 2022Article
- RAS Function in cancer cells: translating membrane biology and biochemistry into new therapeutics.The Biochemical journal · 2020Review
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.