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Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors. 2013
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. melissa.vasbinder@astrazeneca.com
B-Raf represents an attractive target for anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display pERK elevation in nonmutant B-Raf cell lines in vitro.
Related Publications
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
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Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
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Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
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Li Sha, and
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Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
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Bioorganic & medicinal chemistry letters,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
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Bioorganic & medicinal chemistry letters,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
February 2009,
Bioorganic & medicinal chemistry letters,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
October 2009,
Journal of medicinal chemistry,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
April 2014,
Bioorganic & medicinal chemistry letters,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
June 2018,
Journal of medicinal chemistry,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
August 2008,
Bioorganic & medicinal chemistry letters,
Melissa M Vasbinder, and
Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
September 2012,
Organic & biomolecular chemistry,
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Brian Aquila, and
Martin Augustin, and
Huawei Chen, and
Tony Cheung, and
Donald Cook, and
Lisa Drew, and
Benjamin P Fauber, and
Steve Glossop, and
Michael Grondine, and
Edward Hennessy, and
Jeffrey Johannes, and
Stephen Lee, and
Paul Lyne, and
Mario Mörtl, and
Charles Omer, and
Sangeetha Palakurthi, and
Timothy Pontz, and
Jon Read, and
Li Sha, and
Minhui Shen, and
Stefan Steinbacher, and
Haixia Wang, and
Allan Wu, and
Minwei Ye
February 2011,
Bioorganic & medicinal chemistry letters,
