Development of 'DFG-out' inhibitors of gatekeeper mutant kinases

Hwan Geun Choi; Jianming Zhang; Ellen Weisberg; James D. Griffin; Taebo Sim; Nathanael S. Gray

doi:10.1016/j.bmcl.2012.06.036

Development of 'DFG-out' inhibitors of gatekeeper mutant kinases

Hwan Geun Choi, Jianming Zhang, Ellen Weisberg, James D. Griffin, Taebo Sim, Nathanael S. Gray

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.

Original language	English
Pages (from-to)	5297-5302
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2012.06.036
Publication status	Published - 2012 Aug 15

Keywords

Gatekeeper mutant
Kinase inhibitor
T315I Bcr-Abl
Thiazolo[5,4-b]pyridine
Type II inhibitor

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2012.06.036

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title = "Development of 'DFG-out' inhibitors of gatekeeper mutant kinases",

abstract = "HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.",

keywords = "Gatekeeper mutant, Kinase inhibitor, T315I Bcr-Abl, Thiazolo[5,4-b]pyridine, Type II inhibitor",

author = "Choi, {Hwan Geun} and Jianming Zhang and Ellen Weisberg and Griffin, {James D.} and Taebo Sim and Gray, {Nathanael S.}",

note = "Funding Information: We thank Nam Doo Kim for assistance with molecular modeling and Sara Buhrlage for critical reading of the manuscript. We acknowledge research funding from Novartis and NIH (R01 CA130876-02). ",

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doi = "10.1016/j.bmcl.2012.06.036",

language = "English",

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T1 - Development of 'DFG-out' inhibitors of gatekeeper mutant kinases

AU - Choi, Hwan Geun

AU - Zhang, Jianming

AU - Weisberg, Ellen

AU - Griffin, James D.

AU - Sim, Taebo

AU - Gray, Nathanael S.

N1 - Funding Information: We thank Nam Doo Kim for assistance with molecular modeling and Sara Buhrlage for critical reading of the manuscript. We acknowledge research funding from Novartis and NIH (R01 CA130876-02).

PY - 2012/8/15

Y1 - 2012/8/15

N2 - HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.

AB - HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.

KW - Gatekeeper mutant

KW - Kinase inhibitor

KW - T315I Bcr-Abl

KW - Thiazolo[5,4-b]pyridine

KW - Type II inhibitor

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SN - 0960-894X

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

Development of 'DFG-out' inhibitors of gatekeeper mutant kinases

Abstract

Keywords

ASJC Scopus subject areas

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