2. Academic Validation
  3. A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF

A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF

  • Cancer Res. 2010 Oct 15;70(20):8036-44. doi: 10.1158/0008-5472.CAN-10-1366.
Steven Whittaker 1,  Delphine Ménard,  Ruth Kirk,  Lesley Ogilvie,  Douglas Hedley,  Alfonso Zambon,  Filipa Lopes,  Natasha Preece,  Helen Manne,  Sareena Rana,  Maryou Lambros,  Jorge S Reis-Filho,  Richard Marais,  Caroline J Springer
Affiliations

Affiliation

  • 1 Signal Transduction Team, Section of Cell and Molecular Biology, Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
PMID: 20807807 DOI: 10.1158/0008-5472.CAN-10-1366
Abstract

Oncogenic BRaf is a critical driver of proliferation and survival and is thus a validated therapeutic target in Cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, (V600E)BRaf. 1t inhibits signaling downstream of (V600E)BRaf in Cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF Cancer cell lines compared with wild-type BRaf lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of (V600E)BRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRaf human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z