Procaspase-3 activation as an anti-cancer strategy: Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3

Quinn Peterson, Danny C. Hsu, David R. Goode, Chris J. Novotny, Ryan K. Totten, Paul J. Hergenrother

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and inmouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivativeswhere key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.

Original languageEnglish (US)
Pages (from-to)5721-5731
Number of pages11
JournalJournal of Medicinal Chemistry
Volume52
Issue number18
DOIs
StatePublished - Sep 24 2009
Externally publishedYes

Fingerprint

Structure-Activity Relationship
Caspase 3
Neoplasms
Zinc
Cell Culture Techniques
Precision Medicine
Heterografts
Ions
Apoptosis
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Procaspase-3 activation as an anti-cancer strategy : Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3. / Peterson, Quinn; Hsu, Danny C.; Goode, David R.; Novotny, Chris J.; Totten, Ryan K.; Hergenrother, Paul J.

In: Journal of Medicinal Chemistry, Vol. 52, No. 18, 24.09.2009, p. 5721-5731.

Research output: Contribution to journalArticle

@article{f10cf0bc47374a17987fd6a2d1423bcf,
title = "Procaspase-3 activation as an anti-cancer strategy: Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3",
abstract = "A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and inmouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivativeswhere key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.",
author = "Quinn Peterson and Hsu, {Danny C.} and Goode, {David R.} and Novotny, {Chris J.} and Totten, {Ryan K.} and Hergenrother, {Paul J.}",
year = "2009",
month = "9",
day = "24",
doi = "10.1021/jm900722z",
language = "English (US)",
volume = "52",
pages = "5721--5731",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

TY - JOUR

T1 - Procaspase-3 activation as an anti-cancer strategy

T2 - Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3

AU - Peterson, Quinn

AU - Hsu, Danny C.

AU - Goode, David R.

AU - Novotny, Chris J.

AU - Totten, Ryan K.

AU - Hergenrother, Paul J.

PY - 2009/9/24

Y1 - 2009/9/24

N2 - A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and inmouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivativeswhere key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.

AB - A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and inmouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivativeswhere key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.

UR - http://www.scopus.com/inward/record.url?scp=70349433777&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349433777&partnerID=8YFLogxK

U2 - 10.1021/jm900722z

DO - 10.1021/jm900722z

M3 - Article

C2 - 19708658

AN - SCOPUS:70349433777

VL - 52

SP - 5721

EP - 5731

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -