Acylideneoxoindoles

A new class of reversible inhibitors of human transglutaminase 2

Cornelius Klöck, Xi Jin, Kihang Choi, Chaitan Khosla, Peter B. Madrid, Andrew Spencer, Brian C. Raimundo, Paul Boardman, Guido Lanza, John H. Griffin

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had Ki values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.

Original languageEnglish
Pages (from-to)2692-2696
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number9
DOIs
Publication statusPublished - 2011 May 1
Externally publishedYes

Fingerprint

Allosteric Site
Lead compounds
Animal Diseases
Physiology
Celiac Disease
Structure-Activity Relationship
Assays
Animals
Kinetics
transglutaminase 2
Enzymes
Neoplasms
Therapeutics
Lead

Keywords

  • Allostery
  • Celiac sprue
  • Oxoindole
  • Structure-activity relationships
  • Transglutaminase 2

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Acylideneoxoindoles : A new class of reversible inhibitors of human transglutaminase 2. / Klöck, Cornelius; Jin, Xi; Choi, Kihang; Khosla, Chaitan; Madrid, Peter B.; Spencer, Andrew; Raimundo, Brian C.; Boardman, Paul; Lanza, Guido; Griffin, John H.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 9, 01.05.2011, p. 2692-2696.

Research output: Contribution to journalArticle

Klöck, C, Jin, X, Choi, K, Khosla, C, Madrid, PB, Spencer, A, Raimundo, BC, Boardman, P, Lanza, G & Griffin, JH 2011, 'Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 9, pp. 2692-2696. https://doi.org/10.1016/j.bmcl.2010.12.037
Klöck, Cornelius ; Jin, Xi ; Choi, Kihang ; Khosla, Chaitan ; Madrid, Peter B. ; Spencer, Andrew ; Raimundo, Brian C. ; Boardman, Paul ; Lanza, Guido ; Griffin, John H. / Acylideneoxoindoles : A new class of reversible inhibitors of human transglutaminase 2. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 9. pp. 2692-2696.
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