Design, synthesis, and biological evaluation of potent c-Met inhibitors

Noel D. D'Angelo; Steven F. Bellon; Shon K. Booker; Yuan Cheng; Angela Coxon; Celia Dominguez; Ingrid Fellows; Douglas Hoffman; Randall Hungate; Paula Kaplan-Lefko; Matthew R. Lee; Chun Li; Longbin Liu; Elizabeth Rainbeau; Paul J. Reider; Karen Rex; Aaron Siegmund; Yaxiong Sun; Andrew S. Tasker; Ning Xi; Shimin Xu; Yajing Yang; Yihong Zhang; Teresa L. Burgess; Isabelle Dussault; Tae Seong Kim

doi:10.1021/jm8006189

Design, synthesis, and biological evaluation of potent c-Met inhibitors

Noel D. D'Angelo, Steven F. Bellon, Shon K. Booker, Yuan Cheng, Angela Coxon, Celia Dominguez, Ingrid Fellows, Douglas Hoffman, Randall Hungate, Paula Kaplan-Lefko, Matthew R. Lee, Chun Li, Longbin Liu, Elizabeth Rainbeau, Paul J. Reider, Karen Rex, Aaron Siegmund, Yaxiong Sun, Andrew S. Tasker, Ning XiShimin Xu, Yajing Yang, Yihong Zhang, Teresa L. Burgess, Isabelle Dussault, Tae Seong Kim

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

90 Scopus citations

Abstract

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

Original language	English (US)
Pages (from-to)	5766-5779
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	18
DOIs	https://doi.org/10.1021/jm8006189
State	Published - Sep 25 2008
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/jm8006189

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D'Angelo, N. D., Bellon, S. F., Booker, S. K., Cheng, Y., Coxon, A., Dominguez, C., Fellows, I., Hoffman, D., Hungate, R., Kaplan-Lefko, P., Lee, M. R., Li, C., Liu, L., Rainbeau, E., Reider, P. J., Rex, K., Siegmund, A., Sun, Y., Tasker, A. S., ... Kim, T. S. (2008). Design, synthesis, and biological evaluation of potent c-Met inhibitors. Journal of Medicinal Chemistry, 51(18), 5766-5779. https://doi.org/10.1021/jm8006189

@article{d9e1376d1fef45a3af4f6f3c8a3dbdfd,

title = "Design, synthesis, and biological evaluation of potent c-Met inhibitors",

abstract = "c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.",

author = "D'Angelo, {Noel D.} and Bellon, {Steven F.} and Booker, {Shon K.} and Yuan Cheng and Angela Coxon and Celia Dominguez and Ingrid Fellows and Douglas Hoffman and Randall Hungate and Paula Kaplan-Lefko and Lee, {Matthew R.} and Chun Li and Longbin Liu and Elizabeth Rainbeau and Reider, {Paul J.} and Karen Rex and Aaron Siegmund and Yaxiong Sun and Tasker, {Andrew S.} and Ning Xi and Shimin Xu and Yajing Yang and Yihong Zhang and Burgess, {Teresa L.} and Isabelle Dussault and Kim, {Tae Seong}",

year = "2008",

month = sep,

day = "25",

doi = "10.1021/jm8006189",

language = "English (US)",

volume = "51",

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D'Angelo, ND, Bellon, SF, Booker, SK, Cheng, Y, Coxon, A, Dominguez, C, Fellows, I, Hoffman, D, Hungate, R, Kaplan-Lefko, P, Lee, MR, Li, C, Liu, L, Rainbeau, E, Reider, PJ, Rex, K, Siegmund, A, Sun, Y, Tasker, AS, Xi, N, Xu, S, Yang, Y, Zhang, Y, Burgess, TL, Dussault, I & Kim, TS 2008, 'Design, synthesis, and biological evaluation of potent c-Met inhibitors', Journal of Medicinal Chemistry, vol. 51, no. 18, pp. 5766-5779. https://doi.org/10.1021/jm8006189

TY - JOUR

T1 - Design, synthesis, and biological evaluation of potent c-Met inhibitors

AU - D'Angelo, Noel D.

AU - Bellon, Steven F.

AU - Booker, Shon K.

AU - Cheng, Yuan

AU - Coxon, Angela

AU - Dominguez, Celia

AU - Fellows, Ingrid

AU - Hoffman, Douglas

AU - Hungate, Randall

AU - Kaplan-Lefko, Paula

AU - Lee, Matthew R.

AU - Li, Chun

AU - Liu, Longbin

AU - Rainbeau, Elizabeth

AU - Reider, Paul J.

AU - Rex, Karen

AU - Siegmund, Aaron

AU - Sun, Yaxiong

AU - Tasker, Andrew S.

AU - Xi, Ning

AU - Xu, Shimin

AU - Yang, Yajing

AU - Zhang, Yihong

AU - Burgess, Teresa L.

AU - Dussault, Isabelle

AU - Kim, Tae Seong

PY - 2008/9/25

Y1 - 2008/9/25

N2 - c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

AB - c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

Design, synthesis, and biological evaluation of potent c-Met inhibitors

Abstract

All Science Journal Classification (ASJC) codes

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