Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
J Med Chem. 2011 Mar 24;54(6):1836-46. doi: 10.1021/jm101479y. Epub 2011 Feb 22.
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.
通过直接抑制酶或抑制 Raf 的直接底物 MEK（丝裂原活化蛋白激酶）来抑制突变型 B-Raf 信号传导，已在临床前研究中证实可抑制肿瘤生长。最近，用一种选择性 B-Raf 抑制剂治疗携带 B-Raf 突变的黑色素瘤患者，初步证明了这些药物具有抗肿瘤活性。本文描述了四氢萘基衍生化合物作为 Raf 通路在体外和体内的有效抑制剂的设计和优化。这些化合物在啮齿动物中具有良好的药代动力学特性，并能抑制小鼠异种移植模型中 B-Raf 突变型肿瘤的生长。
