Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally Available RORγ Inverse Agonist

Receptor-related orphan receptor
γ (RORγ) has emerged
as an attractive therapeutic target for the treatment of cancer and
inflammatory diseases. Herein, we report our effort on the discovery,
optimization, and evaluation of benzothiazole and benzimidazole derivatives
as novel inverse agonists of RORγ. The representative compound 27h (designated as XY123) potently inhibited the RORγ
transcription activity with a half-maximal inhibitory concentration
(IC50) value of 64 nM and showed excellent selectivity
against other nuclear receptors. 27h also potently suppressed
cell proliferation, colony formation, and the expression of androgen
receptor (AR)-regulated genes in AR-positive prostate cancer cell
lines. In addition, 27h demonstrated good metabolic stability
and a pharmacokinetic property with reasonable oral bioavailability
(32.41%) and moderate half-life (t1/2 =
4.98 h). Significantly, oral administration of compound 27h achieved complete and long-lasting tumor regression in the 22Rv1
xenograft tumor model in mice. Compound 27h may serve
as a new valuable lead compound for further development of drugs for
the treatment of prostate cancer.