American Chemical Society
jm1c00828_si_002.csv (1.52 kB)

Discovery of 2‑(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity

Download (1.52 kB)
posted on 2021-10-13, 15:55 authored by Biao Lu, Dong Liu, Bin Gui, Jun Gou, Huaide Dong, Qiyue Hu, Jun Feng, Yuchang Mao, Xiaodong Shen, Shenglan Wang, Caihua Zhang, Ru Shen, Yinfa Yan, Lei Chen, Huiyun Wang, Di Li, Jiayin Zhang, Minsheng Zhang, Rumin Zhang, Chang Bai, Feng He, Weikang Tao, Suxing Liu
RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure–activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound 17 that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the in vivo antitumor efficacy of an RORγ agonist.