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

doi:10.1016/j.bmcl.2010.12.037

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 journal › Article › peer-review

55 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 K_i 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 language	English
Pages (from-to)	2692-2696
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	9
DOIs	https://doi.org/10.1016/j.bmcl.2010.12.037
Publication status	Published - 2011 May 1
Externally published	Yes

Keywords

Allostery
Celiac sprue
Oxoindole
Structure-activity relationships
Transglutaminase 2

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2010.12.037

Cite this

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title = "Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2",

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.",

keywords = "Allostery, Celiac sprue, Oxoindole, Structure-activity relationships, Transglutaminase 2",

author = "Cornelius Kl{\"o}ck and Xi Jin and Kihang Choi and Chaitan Khosla and Madrid, {Peter B.} and Andrew Spencer and Raimundo, {Brian C.} and Paul Boardman and Guido Lanza and Griffin, {John H.}",

note = "Funding Information: This research was supported by an STTR Grant from the NIH ( DK 1 R41 DK081244 ). ",

year = "2011",

month = may,

day = "1",

doi = "10.1016/j.bmcl.2010.12.037",

language = "English",

volume = "21",

pages = "2692--2696",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T2 - A new class of reversible inhibitors of human transglutaminase 2

AU - Klöck, Cornelius

AU - Jin, Xi

AU - Choi, Kihang

AU - Khosla, Chaitan

AU - Madrid, Peter B.

AU - Spencer, Andrew

AU - Raimundo, Brian C.

AU - Boardman, Paul

AU - Lanza, Guido

AU - Griffin, John H.

N1 - Funding Information: This research was supported by an STTR Grant from the NIH ( DK 1 R41 DK081244 ).

PY - 2011/5/1

Y1 - 2011/5/1

N2 - 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.

AB - 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.

KW - Allostery

KW - Celiac sprue

KW - Oxoindole

KW - Structure-activity relationships

KW - Transglutaminase 2

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DO - 10.1016/j.bmcl.2010.12.037

M3 - Article

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AN - SCOPUS:79955469942

SN - 0960-894X

VL - 21

SP - 2692

EP - 2696

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 9

ER -

Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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