1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity
Karen Miller-Moslin1, Stefan Peukert, Rishi K Jain
1Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. karen.miller@novartis.com
Abstract:
Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based 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 analogues 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 afforded tumor regression in a genetic mouse model of medulloblastoma.
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