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

Abstract

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.

Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer

“…Given the critical roles in multiple inflammatory pathways, RORγ inhibition represents an attractive therapeutic strategy to treat inflammatory diseases . Therefore, a large number of RORγ inhibitors with diverse chemical scaffolds have been reported by many research groups and more than 10 candidates have been advanced into clinical trials in patients with inflammatory or autoimmune disease, − such as compounds 1 – 6 (Figure ). On the other hand, more recent studies also revealed the critical roles of RORγ in the initiation and progression of various cancers, including multiple myeloma, hepatoma, and colorectal, lung, breast, pancreatic, cervical, and prostate cancers. − In CRPC tumors, RORγ is overexpressed and amplified, and functions as a key determinant of AR overexpression and aberrant signaling.…”

Development of Asymmetric Reductive Amination of Unfunctionalized Ketone with Primary Amine

“…Recently, ( R )-2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethan-1-ol ( 1 , in Figure ) has been identified as the key intermediate in the synthesis of a series of pan KRAS inhibitors . The synthesis of this chiral secondary amine, however, encountered some challenges when scaling up (Scheme ).…”

Discovery of Biaryl Amide Derivatives as Potent, Selective, and Orally Bioavailable RORγt Agonists for Cancer Immunotherapy

“…24,25 Therefore, RORγt agonists remain potential tactics to cancer immunotherapy as orally bioavailable small-molecule therapeutics. 26 In addition to LYC-55716, a number of RORγt agonists with diverse scaffolds have been disclosed (Figure 1), including Narylsulfonyl indolines by Scripps Research Institute, 27 benzyloxytricyclic compounds by Bristol Myers Squibb, 28 2-(ortho-substituted benzyl)-indoles from Shanghai Hengrui, 29 tertiary amines 30 and biaryl series 31 from GSK, and so on.…”