A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl

Hwan Geun Choi; Pingda Ren; Francisco Adrian; Fangxian Sun; Hyun Soo Lee; Xia Wang; Qiang Ding; Guobao Zhang; Yongping Xie; Jianming Zhang; Yi Liu; Tove Tuntland; Markus Warmuth; Paul W. Manley; Jürgen Mestan; Nathanael S. Gray; Taebo Sim

doi:10.1021/jm901808w

A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl

Hwan Geun Choi, Pingda Ren, Francisco Adrian, Fangxian Sun, Hyun Soo Lee, Xia Wang, Qiang Ding, Guobao Zhang, Yongping Xie, Jianming Zhang, Yi Liu, Tove Tuntland, Markus Warmuth, Paul W. Manley, Jürgen Mestan, Nathanael S. Gray, Taebo Sim

KU-KIST Graduate School of Converging Science and Technology

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

65 Citations (Scopus)

Abstract

The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.

Original language	English
Pages (from-to)	5439-5448
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	15
DOIs	https://doi.org/10.1021/jm901808w
Publication status	Published - 2010 Aug 12

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Choi, H. G., Ren, P., Adrian, F., Sun, F., Lee, H. S., Wang, X., Ding, Q., Zhang, G., Xie, Y., Zhang, J., Liu, Y., Tuntland, T., Warmuth, M., Manley, P. W., Mestan, J., Gray, N. S., & Sim, T. (2010). A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl. Journal of Medicinal Chemistry, 53(15), 5439-5448. https://doi.org/10.1021/jm901808w

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title = "A type-ii kinase inhibitor capable of inhibiting the T315I {"}Gatekeeper{"} mutant of Bcr-Abl",

abstract = "The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I {"}gatekeeper{"} mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.",

author = "Choi, {Hwan Geun} and Pingda Ren and Francisco Adrian and Fangxian Sun and Lee, {Hyun Soo} and Xia Wang and Qiang Ding and Guobao Zhang and Yongping Xie and Jianming Zhang and Yi Liu and Tove Tuntland and Markus Warmuth and Manley, {Paul W.} and J{\"u}rgen Mestan and Gray, {Nathanael S.} and Taebo Sim",

year = "2010",

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doi = "10.1021/jm901808w",

language = "English",

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T1 - A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl

AU - Choi, Hwan Geun

AU - Ren, Pingda

AU - Adrian, Francisco

AU - Sun, Fangxian

AU - Lee, Hyun Soo

AU - Wang, Xia

AU - Ding, Qiang

AU - Zhang, Guobao

AU - Xie, Yongping

AU - Zhang, Jianming

AU - Liu, Yi

AU - Tuntland, Tove

AU - Warmuth, Markus

AU - Manley, Paul W.

AU - Mestan, Jürgen

AU - Gray, Nathanael S.

AU - Sim, Taebo

PY - 2010/8/12

Y1 - 2010/8/12

N2 - The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.

AB - The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.

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JO - Journal of Medicinal Chemistry

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A type-ii kinase inhibitor capable of inhibiting the T315I "Gatekeeper" mutant of Bcr-Abl

Abstract

ASJC Scopus subject areas

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