Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor‑γ (RORγ) Agonist for Use in Treating Cancer

Retinoic acid receptor-related orphan
receptor γ (RORc, RORγ,
or NR1F3) is the nuclear receptor master transcription factor that
drives the function and development of IL-17-producing T helper cells
(Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells.
Activation of RORγ+ T cells in the tumor microenvironment
is hypothesized to render immune infiltrates more effective at countering
tumor growth. To test this hypothesis, a family of benzoxazines was
optimized to provide LYC-55716 (37c), a potent, selective,
and orally bioavailable small-molecule RORγ agonist. LYC-55716
decreases tumor growth and enhances survival in preclinical tumor
models and was nominated as a clinical development candidate for evaluation
in patients with solid tumors.