Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors

Christophe Antczak; Darren R. Veach; Christina N. Ramirez; Maria A. Minchenko; David Shum; Paul A. Calder; Mark G. Frattini; Bayard Clarkson; Hakim Djaballah

doi:10.1016/j.bmcl.2009.10.085

Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors

Christophe Antczak, Darren R. Veach, Christina N. Ramirez, Maria A. Minchenko, David Shum, Paul A. Calder, Mark G. Frattini, Bayard Clarkson, Hakim Djaballah

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

11 Scopus citations

Abstract

We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML.

Original language	English
Pages (from-to)	6872-6876
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2009.10.085
State	Published - 15 Dec 2009
Externally published	Yes

Keywords

Abl kinase
CML
Inhibitor
Pyridopyrimidines

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10.1016/j.bmcl.2009.10.085

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Antczak, C., Veach, D. R., Ramirez, C. N., Minchenko, M. A., Shum, D., Calder, P. A., Frattini, M. G., Clarkson, B., & Djaballah, H. (2009). Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors. Bioorganic and Medicinal Chemistry Letters, 19(24), 6872-6876. https://doi.org/10.1016/j.bmcl.2009.10.085

@article{cca30cb1dbff48ff9e5943b3151f4ecc,

title = "Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors",

abstract = "We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML.",

keywords = "Abl kinase, CML, Inhibitor, Pyridopyrimidines",

author = "Christophe Antczak and Veach, {Darren R.} and Ramirez, {Christina N.} and Minchenko, {Maria A.} and David Shum and Calder, {Paul A.} and Frattini, {Mark G.} and Bayard Clarkson and Hakim Djaballah",

note = "Funding Information: The authors wish to thank the members of the High Throughput Screening Core Facility for their help during the course of this study. The HTS Core Facility is partially supported by Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research , the Experimental Therapeutics Center of MSKCC , the William Randolph Hearst Fund in Experimental Therapeutics , the Lilian S. Wells Foundation , and by an NIH/NCI Cancer Center Support Grant 5 P30 CA008748-44 . D.V. and B.C. gratefully acknowledge the MeadWestvaco Corporation for financial support.",

year = "2009",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2009.10.085",

language = "English",

volume = "19",

pages = "6872--6876",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

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Antczak, C, Veach, DR, Ramirez, CN, Minchenko, MA, Shum, D, Calder, PA, Frattini, MG, Clarkson, B & Djaballah, H 2009, 'Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 24, pp. 6872-6876. https://doi.org/10.1016/j.bmcl.2009.10.085

Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors. / Antczak, Christophe; Veach, Darren R.; Ramirez, Christina N. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 24, 15.12.2009, p. 6872-6876.

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

TY - JOUR

T1 - Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones

T2 - Toward selective Abl inhibitors

AU - Antczak, Christophe

AU - Veach, Darren R.

AU - Ramirez, Christina N.

AU - Minchenko, Maria A.

AU - Shum, David

AU - Calder, Paul A.

AU - Frattini, Mark G.

AU - Clarkson, Bayard

AU - Djaballah, Hakim

N1 - Funding Information: The authors wish to thank the members of the High Throughput Screening Core Facility for their help during the course of this study. The HTS Core Facility is partially supported by Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research , the Experimental Therapeutics Center of MSKCC , the William Randolph Hearst Fund in Experimental Therapeutics , the Lilian S. Wells Foundation , and by an NIH/NCI Cancer Center Support Grant 5 P30 CA008748-44 . D.V. and B.C. gratefully acknowledge the MeadWestvaco Corporation for financial support.

PY - 2009/12/15

Y1 - 2009/12/15

N2 - We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML.

AB - We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML.

KW - Abl kinase

KW - CML

KW - Inhibitor

KW - Pyridopyrimidines

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U2 - 10.1016/j.bmcl.2009.10.085

DO - 10.1016/j.bmcl.2009.10.085

M3 - Article

C2 - 19889540

AN - SCOPUS:71849116723

SN - 0960-894X

VL - 19

SP - 6872

EP - 6876

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 24

ER -

Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors

Abstract

Keywords

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