RO4987655

RO4987655是MEK高选择性的小分子抑制剂,IC50值为5 nM[1].

RO4987655在5位有一个独特的3-oxo-[1,2]oxazinan-2-ylmethyl 基团.相对其他400种激酶,RO4987655对MEK具有高选择性.同时,RO4987655是MEK的非竞争性抑制剂.在ATP缺乏或存在时都对MEK具有较高的亲和力.RO4987655对多种肿瘤细胞都有很强的抗增殖作用,包括COLO205\HT29\QG56\MIA和C32,IC50值分别为0.86 nM\1.7 nM\9.5 nM\3.3 nM和8.4 nM.此外,RO4987655被发现在多种人类肿瘤异种移植模型中都具有抗肿瘤活性.在HT-29人结肠癌异种移植物中,RO4987655强烈抑制pERK的形成,引起肿瘤消退[ 1,2 ].

RO4987655正在进行I期临床试验.试验表明,RO4987655对BRAF野生型黑色素瘤和BRAF V600突变型黑色素瘤的患者都有临床活性.它也对KRAS突变的非小细胞肺癌患者有效,但对KRAS突变的结直肠癌无效[ 2 ].

参考文献：
[1] Isshiki Y, Kohchi Y, Iikura H, Matsubara Y, Asoh K, Murata T, Kohchi M, Mizuguchi E, Tsujii S, Hattori K, Miura T, Yoshimura Y, Aida S, Miwa M, Saitoh R, Murao N, Okabe H, Belunis C, Janson C, Lukacs C, Schück V, Shimma N.  Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1795-801.
[2] Zimmer L, Barlesi F, Martinez-Garcia M, Dieras V, Schellens JH, Spano JP, Middleton MR, Calvo E, Paz-Ares L, Larkin J, Pacey S, Venturi M, Kraeber-Bodere F, Tessier JJ, Eberhardt WE, Paques M, Guarin E, Meresse Naegelen V, Soria JC.  Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected advanced cancer patients with RAS-RAF mutations. Clin Cancer Res. 2014 Jun 19. pii: clincanres.0341.2014.