RO4929097

RO4929097是γ分泌酶（γ-secretase）的小分子抑制剂，IC50和EC50值分别为4 nM和5 nM，对密切相关的蛋白酶没有体外抑制活性。相对于75种其它各种类型的蛋白酶，RO4929097对γ分泌酶具有大于100倍的选择性[1]。RO4929097与γ分泌酶结合，抑制其蛋白酶活性，从而阻断Notch的切割，减少Notch信号。Notch信号通路的上调促进多种肿瘤的发生。

据报道，RO4929097在体外和体内均具有潜在的抗肿瘤活性。RO4929097抑制黑色素瘤细胞的生长和人原发性黑色素瘤异种移植物的肿瘤形成[2]。在乳腺癌细胞中，RO4929097减慢细胞增殖，减少集落形成[1]。此外，在结直肠癌、胰腺癌、肺癌和黑色素瘤异种移植模型中，RO4929097抑制肿瘤形成[1, 2]。在多个I / II期临床试验中，RO4929097单独给药或与其它抗癌剂联合给药用于治疗晚期实体瘤患者[3-8]。

参考文献：
1. Luistro L, He W, Smith M et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009; 69: 7672-7680.
2. Huynh C, Poliseno L, Segura MF et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 2011; 6: e25264.
3. Richter S, Bedard PL, Chen EX et al. A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). Invest New Drugs 2014; 32: 243-249.
4. Sahebjam S, Bedard PL, Castonguay V et al. A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br J Cancer 2013; 109: 943-949.
5. Diaz-Padilla I, Hirte H, Oza AM et al. A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest New Drugs 2013; 31: 1182-1191.
6. Tolcher AW, Messersmith WA, Mikulski SM et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 2012; 30: 2348-2353.
7. Strosberg JR, Yeatman T, Weber J et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer 2012; 48: 997-1003.
8. Kolb EA, Gorlick R, Keir ST et al. Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a gamma-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer 2012; 58: 815-818.