Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citation
    • Author/Keyword
  • News
    • Cancer Discovery News
Small Molecule Therapeutics

Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

Liangxian Cao, Marla Weetall, Christopher Trotta, Katherine Cintron, Jiyuan Ma, Min Jung Kim, Bansri Furia, Charles Romfo, Jason D. Graci, Wencheng Li, Joshua Du, Josephine Sheedy, Jean Hedrick, Nicole Risher, Shirley Yeh, Hongyan Qi, Tamil Arasu, Seongwoo Hwang, William Lennox, Ronald Kong, Janet Petruska, Young-Choon Moon, John Babiak, Thomas W. Davis, Allan Jacobson, Neil G. Almstead, Art Branstrom, Joseph M. Colacino and Stuart W. Peltz
Liangxian Cao
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Liangxian Cao
  • For correspondence: lcao@ptcbio.com
Marla Weetall
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher Trotta
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katherine Cintron
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jiyuan Ma
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Min Jung Kim
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bansri Furia
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles Romfo
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jason D. Graci
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wencheng Li
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joshua Du
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Josephine Sheedy
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean Hedrick
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicole Risher
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shirley Yeh
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hongyan Qi
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tamil Arasu
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seongwoo Hwang
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William Lennox
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ronald Kong
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Janet Petruska
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Young-Choon Moon
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Babiak
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas W. Davis
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Allan Jacobson
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Allan Jacobson
Neil G. Almstead
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Art Branstrom
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph M. Colacino
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Joseph M. Colacino
Stuart W. Peltz
PTC Therapeutics, Inc., South Plainfield, New Jersey.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.MCT-18-0863 Published January 2019
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated in the clinic for treatment of solid tumors. To guide precision cancer treatment, we performed extensive biological characterization of the activity of PTC299 and demonstrated that inhibition of VEGF production and cell proliferation by PTC299 is linked to a decrease in uridine nucleotides by targeting dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH inhibitors that were identified using in vitro enzyme assays, PTC299 is a more potent inhibitor of DHODH in isolated mitochondria suggesting that mitochondrial membrane lipid engagement in the DHODH conformation in situ is required for its optimal activity. PTC299 has broad and potent activity against hematologic cancer cells in preclinical models, reflecting a reduced pyrimidine nucleotide salvage pathway in leukemia cells. Archived serum samples from patients treated with PTC299 demonstrated increased levels of dihydroorotate, the substrate of DHODH, indicating target engagement in patients. PTC299 has advantages over previously reported DHODH inhibitors, including greater potency, good oral bioavailability, and lack of off-target kinase inhibition and myelosuppression, and thus may be useful for the targeted treatment of hematologic malignancies.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received August 1, 2018.
  • Revision received August 22, 2018.
  • Accepted October 17, 2018.
  • Published first October 23, 2018.
  • ©2018 American Association for Cancer Research.
View Full Text
PreviousNext
Back to top
Molecular Cancer Therapeutics: 18 (1)
January 2019
Volume 18, Issue 1
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Editorial Board (PDF)

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
Citation Tools
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Liangxian Cao, Marla Weetall, Christopher Trotta, Katherine Cintron, Jiyuan Ma, Min Jung Kim, Bansri Furia, Charles Romfo, Jason D. Graci, Wencheng Li, Joshua Du, Josephine Sheedy, Jean Hedrick, Nicole Risher, Shirley Yeh, Hongyan Qi, Tamil Arasu, Seongwoo Hwang, William Lennox, Ronald Kong, Janet Petruska, Young-Choon Moon, John Babiak, Thomas W. Davis, Allan Jacobson, Neil G. Almstead, Art Branstrom, Joseph M. Colacino and Stuart W. Peltz
Mol Cancer Ther January 1 2019 (18) (1) 3-16; DOI: 10.1158/1535-7163.MCT-18-0863

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties
Liangxian Cao, Marla Weetall, Christopher Trotta, Katherine Cintron, Jiyuan Ma, Min Jung Kim, Bansri Furia, Charles Romfo, Jason D. Graci, Wencheng Li, Joshua Du, Josephine Sheedy, Jean Hedrick, Nicole Risher, Shirley Yeh, Hongyan Qi, Tamil Arasu, Seongwoo Hwang, William Lennox, Ronald Kong, Janet Petruska, Young-Choon Moon, John Babiak, Thomas W. Davis, Allan Jacobson, Neil G. Almstead, Art Branstrom, Joseph M. Colacino and Stuart W. Peltz
Mol Cancer Ther January 1 2019 (18) (1) 3-16; DOI: 10.1158/1535-7163.MCT-18-0863
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Conclusion
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Molecular Inhibitor of QSOX1 Suppresses Tumor Growth
  • Salicylanilide as an Autophagy Inducer for CRPC Therapy
  • CDK4/6 Inhibition in Early-Stage Breast Cancer
Show more Small Molecule Therapeutics
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2019 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement