Skip to main content
  • AACR Publications
    • 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

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • 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
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Precision Medicine and Therapeutic Resistance
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Research Watch

Cryo-EM Structures Reveal Mechanism of Anticancer MCT1 Inhibitors

DOI: 10.1158/2159-8290.CD-RW2021-004 Published March 2021
  • Article
  • Info & Metrics
  • PDF
Loading
  • Major Finding: Structural and biochemical analyses uncovered the substrate binding and transport mechanisms of MCT1.

  • Concept: MCT1–Basigin-2 inhibitors caused different structural changes but were all competitive inhibitors.

  • Impact: This study reveals the inhibition mechanism of MCTs, which can be targeted for anticancer therapies.

Monocarboxylate transporters (MCT) are key components involved in monocarboxylate absorption and redistribution in mammalian cells and are known to play a role in cancer development by increasing lactate shuttling, prompting the development of MCT inhibitors. In an effort to better understand the mechanism by which these inhibitors reduce MCT activity, Wang, Jiang, and colleagues determined the cryo-EM structures of the human MCT1 complex (comprised of MCT1 and the chaperone protein Basigin-2) and the MCT1 complex bound to lactate or to the inhibitors AZD3965, BAY-8002, and 7ACC2 at resolutions of 3.0 to 3.3. Comparison of cryo-EM structures showed that substrate translocation occurred via protonation-dependent rigid-body rotation of two domains to expose a binding site on each side of the membrane. This idea was supported by the finding that the complex adopted a distinct outward-open structure when lactate or the inhibitors BAY8002 or AZD3965 were bound and an inward-open structure when the inhibitor 7ACC2 was bound. Despite these structural differences, all the inhibitors blocked MCT1 activity via competitive inhibition. This was supported by a structural comparison between lactate- and inhibitor-bound human MCT1. Notably, AZD3965 (which is currently in phase I clinical trials as an anticancer therapy) is known to have subtype-specific sensitivities as it inhibits MCT1/2, but not MCT4. The structural mapping of the key residues involved in AZD3965 binding suggests this could be attributed to sequence variation between MCT subtypes. In summary, this study shows how three MCT1 inhibitors interact with the MCT1 complex to disrupt normal transporter activity. The structures of human MCT1–Basigin-2 bound to the MCT1 inhibitors provide key insight into the molecular mechanism of how substrate translocation is blocked, providing a strong foundation for the structure-guided development of MCT1 inhibitors for cancer treatment.

Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 2020;184:370–83.E13.

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2021 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 11 (3)
March 2021
Volume 11, Issue 3
  • 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 Cancer Discovery 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.
Cryo-EM Structures Reveal Mechanism of Anticancer MCT1 Inhibitors
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Cryo-EM Structures Reveal Mechanism of Anticancer MCT1 Inhibitors
Cancer Discov March 1 2021 (11) (3) 529; DOI: 10.1158/2159-8290.CD-RW2021-004

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Cryo-EM Structures Reveal Mechanism of Anticancer MCT1 Inhibitors
Cancer Discov March 1 2021 (11) (3) 529; DOI: 10.1158/2159-8290.CD-RW2021-004
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
    • Notes
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

Research Watch

  • Cell-Intrinsic Programs Partition Nutrients in Tumor Microenvironment
  • Extrachromosomal DNA Can Promote Oncogene Transcription in Trans
  • Transient Rest Reverses Exhaustion of Chimeric Antigen Receptor T Cells
Show more Research Watch

Structural Biology

  • Structures Identify Selpercatinib and Pralsetinib Resistance Mechanisms
  • BI-3802 Promotes Polymerization and Degradation of Oncogenic BCL6
Show more Structural Biology
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement