2. Academic Validation
  3. Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors

  • J Med Chem. 2011 Mar 24;54(6):1836-46. doi: 10.1021/jm101479y.
Alexandra E Gould 1,  Ruth Adams,  Sharmila Adhikari,  Kathleen Aertgeerts,  Roushan Afroze,  Christopher Blackburn,  Emily F Calderwood,  Ryan Chau,  Jouhara Chouitar,  Matthew O Duffey,  Dylan B England,  Cheryl Farrer,  Nancy Forsyth,  Khristofer Garcia,  Jeffery Gaulin,  Paul D Greenspan,  Ribo Guo,  Sean J Harrison,  Shih-Chung Huang,  Natalia Iartchouk,  Dave Janowick,  Mi-Sook Kim,  Bheemashankar Kulkarni,  Steven P Langston,  Jane X Liu,  Li-Ting Ma,  Saurabh Menon,  Hirotake Mizutani,  Erin Paske,  Christelle C Renou,  Mansoureh Rezaei,  R Scott Rowland,  Michael D Sintchak,  Michael D Smith,  Stephen G Stroud,  Ming Tregay,  Yuan Tian,  Ole P Veiby,  Tricia J Vos,  Stepan Vyskocil,  Juliet Williams,  Tianlin Xu,  Johnny J Yang,  Jason Yano,  Hongbo Zeng,  Dong Mei Zhang,  Qin Zhang,  Katherine M Galvin
Affiliations

Affiliation

  • 1 Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. sandy.gould@mpi.com
PMID: 21341678 DOI: 10.1021/jm101479y
Abstract

Inhibition of mutant B-Raf signaling, through either direct inhibition of the Enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

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