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

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.