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Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.

ABSTRACT: The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

SUBMITTER: Wenglowsky S 

PROVIDER: S-EPMC4017973 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.

Wenglowsky Steve S   Ren Li L   Ahrendt Kateri A KA   Laird Ellen R ER   Aliagas Ignacio I   Alicke Bruno B   Buckmelter Alex J AJ   Choo Edna F EF   Dinkel Victoria V   Feng Bainian B   Gloor Susan L SL   Gould Stephen E SE   Gross Stefan S   Gunzner-Toste Janet J   Hansen Joshua D JD   Hatzivassiliou Georgia G   Liu Bonnie B   Malesky Kim K   Mathieu Simon S   Newhouse Brad B   Raddatz Nicholas J NJ   Ran Yingqing Y   Rana Sumeet S   Randolph Nikole N   Risom Tyler T   Rudolph Joachim J   Savage Scott S   Selby LeAnn T LT   Shrag Michael M   Song Kyung K   Sturgis Hillary L HL   Voegtli Walter C WC   Wen Zhaoyang Z   Willis Brandon S BS   Woessner Richard D RD   Wu Wen-I WI   Young Wendy B WB   Grina Jonas J  

ACS medicinal chemistry letters 20110308 5

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On  ...[more]

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