3TV4

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

Wenglowsky, S., Ren, L., Ahrendt, K.A., Laird, E.R., Aliagas, I., Alicke, B., Buckmelter, A.J., Choo, E.F., Dinkel, V., Feng, B., Gloor, S.L., Gould, S.E., Gross, S., Gunzner-Toste, J., Hansen, J.D., Hatzivassiliou, G., Liu, B., Malesky, K., Mathieu, S., Newhouse, B., Raddatz, N.J., Ran, Y., Rana, S., Randolph, N., Risom, T., Rudolph, J., Savage, S., Selby, L.T., Shrag, M., Song, K., Sturgis, H.L., Voegtli, W.C., Wen, Z., Willis, B.S., Woessner, R.D., Wu, W.I., Young, W.B., Grina, J.

(2011) ACS Med Chem Lett 2: 342-347

• PubMed: 24900315 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1021/ml200025q
• Primary Citation of Related Structures:  
  3TV4, 3TV6


• PubMed 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.

   View More

---

Organizational Affiliation: 

Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.