ArticlePloS one2011
Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Protein Prenyltransferases and Their Inhibitors: Structural and Functional Characterization.International journal of molecular sciences · 2022Review
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- Targeting prenylation inhibition through the mevalonate pathway.RSC medicinal chemistry · 2020Review
- Discussion Addendum for: Phosphine-Catalyzed [4 + 2] Annulation: Synthesis of Ethyl 6-Phenyl-1-tosyl-1,2,5,6-tetrahydropyridine-3-carboxylate.Organic syntheses; an annual publication of satisfactory methods for the preparation of organic chemicals · 2019Article
- Phosphine Organocatalysis.Chemical reviews · 2018Review
- Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies.Chemical reviews · 2018Article
- Nucleophilic Chiral Phosphines: Powerful and Versatile Catalysts for Asymmetric Annulations.Aldrichimica acta · 2016Article
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- Approaches of targeting Rho GTPases in cancer drug discovery.Expert opinion on drug discovery · 2015Review
- Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs.Chemical communications (Cambridge, England) · 2013Article
- In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells.BMC cancer · 2013Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21(CIP1/WAF1) level in human cancer cells. P61-E7 also increases p27(Kip1) protein level and inhibits phosphorylation of p27(Kip1) on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21(CIP1/WAF1) and p27(Kip1) by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells.
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