Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: An X-ray and nmr investigation

Yonghui Zhang, Rong Cao, Fenglin Yin, Michael P. Hudock, Rey Ting Guo, Kilannin Krysiak, Sujoy Mukherjee, Yi Gui Gao, Howard Robinson, Yongcheng Song, Joo Hwan No, Kyle Bergan, Annette Leon, Lauren Cass, Amanda Goddard, Ting Kai Chang, Fu Yang Lin, Ermond Van Beek, Socrates Papapoulos, Andrew H.J. WangTadahiko Kubo, Mitsuo Ochi, Dushyant Mukkamala, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

Original languageEnglish (US)
Pages (from-to)5153-5162
Number of pages10
JournalJournal of the American Chemical Society
Volume131
Issue number14
DOIs
StatePublished - Apr 15 2009

Fingerprint

Geranyltranstransferase
Farnesyltranstransferase
Diphosphonates
Cell growth
Transferases
inhibitor
X-Rays
enzyme
Proteins
Enzyme inhibition
X rays
invasiveness
protein
calorimetry
Calorimetry
Titration
tumor
targeting
nuclear magnetic resonance
Tumors

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors : An X-ray and nmr investigation. / Zhang, Yonghui; Cao, Rong; Yin, Fenglin; Hudock, Michael P.; Guo, Rey Ting; Krysiak, Kilannin; Mukherjee, Sujoy; Gao, Yi Gui; Robinson, Howard; Song, Yongcheng; No, Joo Hwan; Bergan, Kyle; Leon, Annette; Cass, Lauren; Goddard, Amanda; Chang, Ting Kai; Lin, Fu Yang; Beek, Ermond Van; Papapoulos, Socrates; Wang, Andrew H.J.; Kubo, Tadahiko; Ochi, Mitsuo; Mukkamala, Dushyant; Oldfield, Eric.

In: Journal of the American Chemical Society, Vol. 131, No. 14, 15.04.2009, p. 5153-5162.

Research output: Contribution to journalArticle

Zhang, Y, Cao, R, Yin, F, Hudock, MP, Guo, RT, Krysiak, K, Mukherjee, S, Gao, YG, Robinson, H, Song, Y, No, JH, Bergan, K, Leon, A, Cass, L, Goddard, A, Chang, TK, Lin, FY, Beek, EV, Papapoulos, S, Wang, AHJ, Kubo, T, Ochi, M, Mukkamala, D & Oldfield, E 2009, 'Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: An X-ray and nmr investigation', Journal of the American Chemical Society, vol. 131, no. 14, pp. 5153-5162. https://doi.org/10.1021/ja808285e
Zhang, Yonghui ; Cao, Rong ; Yin, Fenglin ; Hudock, Michael P. ; Guo, Rey Ting ; Krysiak, Kilannin ; Mukherjee, Sujoy ; Gao, Yi Gui ; Robinson, Howard ; Song, Yongcheng ; No, Joo Hwan ; Bergan, Kyle ; Leon, Annette ; Cass, Lauren ; Goddard, Amanda ; Chang, Ting Kai ; Lin, Fu Yang ; Beek, Ermond Van ; Papapoulos, Socrates ; Wang, Andrew H.J. ; Kubo, Tadahiko ; Ochi, Mitsuo ; Mukkamala, Dushyant ; Oldfield, Eric. / Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors : An X-ray and nmr investigation. In: Journal of the American Chemical Society. 2009 ; Vol. 131, No. 14. pp. 5153-5162.
@article{00a82d127a1d47c487358c44de59eec2,
title = "Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: An X-ray and nmr investigation",
abstract = "Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.",
author = "Yonghui Zhang and Rong Cao and Fenglin Yin and Hudock, {Michael P.} and Guo, {Rey Ting} and Kilannin Krysiak and Sujoy Mukherjee and Gao, {Yi Gui} and Howard Robinson and Yongcheng Song and No, {Joo Hwan} and Kyle Bergan and Annette Leon and Lauren Cass and Amanda Goddard and Chang, {Ting Kai} and Lin, {Fu Yang} and Beek, {Ermond Van} and Socrates Papapoulos and Wang, {Andrew H.J.} and Tadahiko Kubo and Mitsuo Ochi and Dushyant Mukkamala and Eric Oldfield",
year = "2009",
month = "4",
day = "15",
doi = "10.1021/ja808285e",
language = "English (US)",
volume = "131",
pages = "5153--5162",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors

T2 - An X-ray and nmr investigation

AU - Zhang, Yonghui

AU - Cao, Rong

AU - Yin, Fenglin

AU - Hudock, Michael P.

AU - Guo, Rey Ting

AU - Krysiak, Kilannin

AU - Mukherjee, Sujoy

AU - Gao, Yi Gui

AU - Robinson, Howard

AU - Song, Yongcheng

AU - No, Joo Hwan

AU - Bergan, Kyle

AU - Leon, Annette

AU - Cass, Lauren

AU - Goddard, Amanda

AU - Chang, Ting Kai

AU - Lin, Fu Yang

AU - Beek, Ermond Van

AU - Papapoulos, Socrates

AU - Wang, Andrew H.J.

AU - Kubo, Tadahiko

AU - Ochi, Mitsuo

AU - Mukkamala, Dushyant

AU - Oldfield, Eric

PY - 2009/4/15

Y1 - 2009/4/15

N2 - Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

AB - Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

UR - http://www.scopus.com/inward/record.url?scp=67749130945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67749130945&partnerID=8YFLogxK

U2 - 10.1021/ja808285e

DO - 10.1021/ja808285e

M3 - Article

C2 - 19309137

AN - SCOPUS:67749130945

VL - 131

SP - 5153

EP - 5162

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 14

ER -