Supplementary Table 1 from A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF

Whittaker, Steven; Ménard, Delphine; Kirk, Ruth; Ogilvie, Lesley; Hedley, Douglas; Zambon, Alfonso; Lopes, Filipa; Preece, Natasha; Manne, Helen; Rana, Sareena; Lambros, Maryou; Reis-Filho, Jorge S.; Marais, Richard; Springer, Caroline J.

doi:10.1158/0008-5472.22385499.v1

00085472can101366-sup-stab_1.pdf (68.79 kB)

Supplementary Table 1 from A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of ^V600EBRAF

journal contribution

posted on 2023-03-30, 19:53 authored by Steven Whittaker, 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

Supplementary Table 1 from A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of ^V600EBRAF

History

ARTICLE 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, V600EBRAF. 1t inhibits signaling downstream of V600EBRAF 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 V600EBRAF-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. Cancer Res; 70(20); 8036–44. ©2010 AACR.