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
  • 1. Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States. [email protected]
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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