2. Academic Validation
  3. 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity

1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity

  • J Med Chem. 2009 Jul 9;52(13):3954-68. doi: 10.1021/jm900309j.
Karen Miller-Moslin 1,  Stefan Peukert,  Rishi K Jain,  Michael A McEwan,  Rajesh Karki,  Luis Llamas,  Naeem Yusuff,  Feng He,  Yanhong Li,  Yingchuan Sun,  Miao Dai,  Lawrence Perez,  Walter Michael,  Tao Sheng,  Huangshu Lei,  Rui Zhang,  Juliet Williams,  Aaron Bourret,  Arun Ramamurthy,  Jing Yuan,  Ribo Guo,  Melissa Matsumoto,  Anthony Vattay,  Wieslawa Maniara,  Adam Amaral,  Marion Dorsch,  Joseph F Kelleher 3rd
Affiliations

Affiliation

  • 1 Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. karen.miller@novartis.com
PMID: 19469545 DOI: 10.1021/jm900309j
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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