molecules of the month

The Lycera ROR gamma agonist, cintirorgon (LYC-55716), is a first-in-class phase 1b clinical candidate for cancer immunotherapy (in combination with pembrolizumab in NSCLC). ROR gamma antagonists have been extensively pursued and studied for autoimmune conditions, but ROR gamma agonists have also been recently pursued for “pro-inflammatory” cancer immunotherapy. An interesting aspect of this story is that the agonists are derived from small changes to antagonists through replacement of an amide by groups without an H-bond donor. The H-bond donor of antagonist amide is hypothesized to be important to disrupting the structure of the nuclear receptor and disfavoring co-activator binding.