Skip to main content
  • AACR Publications
    • 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
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
  • AACR Publications
    • 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

Search

  • Advanced search
Cancer Research
Cancer Research

Advanced Search

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Focus on Computer Resources
    • 75th Anniversary
    • Meeting Abstracts
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • OnlineFirst
    • Editors' Picks
    • Citations
    • Author/Keyword
  • News
    • Cancer Discovery News
Experimental and Molecular Therapeutics

Abstract 3011: Development of selective small-molecule inhibitors of cellular MALT1 protease activity

Fredrik G. Oberg, Sofia Karlstrom, Ian Henderson, Ellen Hewitt, Anders Kallin, Susanne Sedig, Jimmy Lindberg, Anna-Karin Sohlenius-Sternbeck, Richard Bethell and Mark Albertella
Fredrik G. Oberg
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sofia Karlstrom
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ian Henderson
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ellen Hewitt
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anders Kallin
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Sedig
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jimmy Lindberg
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anna-Karin Sohlenius-Sternbeck
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard Bethell
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark Albertella
Medivir AB, Huddinge, Sweden.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1538-7445.AM2016-3011 Published July 2016
  • Article
  • Info & Metrics
Loading
Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

Abstract

Background: The aim of this study was to develop potent, selective and cell-permeable inhibitors of MALT1 protease activity. MALT1 is an Arg-specific protease that cleaves multiple substrates, acting as a key component in T- and B-cell receptor signaling in lymphocytes. MALT1 protease activity is reported to mediate normal and disease-associated lymphocyte proliferation and survival as part of the CARMA-1/BCL-10/MALT1 (CBM) signaling complex, making MALT1 an attractive therapeutic target. Constitutive MALT1 activity is a hallmark of Diffuse Large B Cell Lymphoma of the activated B cell type (ABC-DLBCL). This aberrant activation is observed as a consequence of mutations in CARMA-1/CARD11, and in multiple regulatory proteins upstream of the CBM complex.

Methods: MALT1 enzyme assay with Ac-Leu-Arg-Ser-Arg-AMC as substrate was used to measure Ki. Selectivity towards other Arg-specific proteases was measured by inhibition of Trypsin and Thrombin. For determination of cellular potency the ABC-DLBCL cell line OCI-LY3, carrying the L251P mutation of CARMA-1/CARD11, was used. A MALT1 cell assay to measure A20 substrate cleavage was adapted to capillary electrophoresis and quantification. MALT1 down-stream signaling was measured by inhibition of IL-6 expression.

Results: Published inhibitors of MALT1 were profiled for potency, selectivity, DMPK properties and activity in cell-based assays, and showed several drawbacks such as low MALT1 activity, low cell permeability and/or selectivity. We developed several novel reversible small molecule inhibitors of MALT1 with Ki <20 nM and high selectivity against Trypsin and Thrombin. Compounds show inhibition of intracellular MALT1 activity with potencies <300nM in the A20 cleavage assay, as well as inhibition of IL-6 expression. Intracellular inhibition of MALT1 activity requires both potent inhibition of MALT1 and cell permeability (estimated by Caco-2 permeability), e.g. compound A with MALT1 Ki = 16nM, Trypsin Ki>100μM, Thrombin Ki>100μM, and Caco-2 Papp = 1×10−6cm/s shows intracellular A20 cleavage IC50 = 1100nM, whereas compound B with MALT1 Ki = 47nM and Caco-2 Papp = 5.6×10−6cm/s, displays intracellular A20 cleavage IC50 = 600nM. We observe a clear dissociation between intracellular inhibition of MALT1 and inhibition of cell proliferation of DLBCL cell lines of ABC-type with constitutive MALT1 activity, e.g. compound C (MALT1 Ki = 35nM, Trypsin Ki>100μM, Thrombin Ki>100μM and intracellular A20 cleavage IC50 = 260nM) inhibits the proliferation of OCI-LY3 cells and TMD8 cells with CC50 values of 73μM and 96μM respectively, after 5 days exposure.

Conclusion: Inhibition of MALT1 protease activity did not translate into significant anti-proliferative effects in DLBCL cell lines. These new MALT1 inhibitors provide the

opportunity to test other therapeutic hypotheses involving the targeting of MALT1 protease activity.

Citation Format: Fredrik G. Oberg, Sofia Karlstrom, Ian Henderson, Ellen Hewitt, Anders Kallin, Susanne Sedig, Jimmy Lindberg, Anna-Karin Sohlenius-Sternbeck, Richard Bethell, Mark Albertella. Development of selective small-molecule inhibitors of cellular MALT1 protease activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3011.

  • ©2016 American Association for Cancer Research.
Previous
Back to top
Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
  • Table of Contents
  • Index by Author

Sign up for alerts

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Research 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.
Abstract 3011: Development of selective small-molecule inhibitors of cellular MALT1 protease activity
(Your Name) has forwarded a page to you from Cancer Research
(Your Name) thought you would be interested in this article in Cancer Research.
Citation Tools
Abstract 3011: Development of selective small-molecule inhibitors of cellular MALT1 protease activity
Fredrik G. Oberg, Sofia Karlstrom, Ian Henderson, Ellen Hewitt, Anders Kallin, Susanne Sedig, Jimmy Lindberg, Anna-Karin Sohlenius-Sternbeck, Richard Bethell and Mark Albertella
Cancer Res July 15 2016 (76) (14 Supplement) 3011; DOI: 10.1158/1538-7445.AM2016-3011

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Abstract 3011: Development of selective small-molecule inhibitors of cellular MALT1 protease activity
Fredrik G. Oberg, Sofia Karlstrom, Ian Henderson, Ellen Hewitt, Anders Kallin, Susanne Sedig, Jimmy Lindberg, Anna-Karin Sohlenius-Sternbeck, Richard Bethell and Mark Albertella
Cancer Res July 15 2016 (76) (14 Supplement) 3011; DOI: 10.1158/1538-7445.AM2016-3011
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
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Experimental and Molecular Therapeutics

  • Abstract SY14-03: Anaplastic lymphoma kinase (ALK): Normal biology and role in hematopoietic malignancies
  • Abstract SY18-01: Targeting the p53-MDM2 interaction for cancer therapy
  • Abstract SSY01-04: Discovery and validation of genome-wide genetic signatures of chemotherapy susceptibility: A translational model
Show more 3

Poster Presentations - Proffered Abstracts

  • Abstract LB-236: Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013
  • Abstract LB-001: Impact of direct physician engagement with racial/ethnic minorities for oncology clinical trial access and accrual model
  • Abstract LB-107: EV-TRACK: transparent reporting and centralizing knowledge of extracellular vesicles to support the validation of extracellular vesicle biomarkers in cancer research
Show more 3

Poster Presentations - Novel Targets and Pathways

  • Abstract 3039: Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II
  • Abstract 3040: A novel methoxyflavanone from a Chinese medicinal herb (Perilla frutescens) induces G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma cells
  • Abstract 3038: Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)
Show more 3
  • Home
  • Alerts
  • Feedback
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

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

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians
  • Reviewers

About Cancer Research

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

Copyright © 2018 by the American Association for Cancer Research.

Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

Advertisement