Miller-Moslin, Karen, Peukert, Stefan, Mcewan, Michael, Karki, Rajesh, Llamas, Luis, Yusuff, Naeem, Dai, Miao, Perez, Lawrence, Michael, Walter, Sheng, Tao, Williams, Juliet, Dorsch, Marion, Bourret, Aaron, Ramamurthy, Arun, Yuan, Jing, Guo, Ribo, Matsumoto, Melissa, Vattay, Anthony, Maniara, Wieslawa, Amaral, Adam and Kelleher Iii, Joseph (2009) 1-Amino-4-benzylphthalazines as novel, orally bioavailable Smoothened antagonists with anti-tumor activity. Journal of Medicinal Chemistry, 52 (13). pp. 3954-3968.

Abstract

Abnormal activation of the Hh pathway has been linked to sevral types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route towards novel anti-cancer therapeutics. A cell-base screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogs were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also offered tumor regression in a genetic mouse model of medulloblastoma.

Item Type:	Article
Keywords:	hedgehog inhibitor, Smoothened
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/3082