ITRI-90 is an orally active androgen receptor (AR) PROTAC degrader. It effectively degrades full-length AR (AR-FL) and its splice variant AR-V7 proteins via the ubiquitin-proteasome system, thereby inhibiting AR transcriptional activity and its target gene expression. This compound significantly suppresses the proliferation of prostate cancer cells, including those resistant to Enzalutamide, and induces apoptosis. ITRI-90 demonstrates favorable pharmacokinetic properties and exhibits strong antitumor efficacy in vivo, making it valuable for prostate cancer research.

ITRI-90 demonstrates a significant reduction in the levels of full-length androgen receptor (AR-FL) and splice variant AR-V(ΔLBD) proteins when administered at concentrations of 0-20 μM for 24 hours in LNCaP, CWR22Rv1, and VCaP cells. The half-maximal degradation concentration (DC50) for AR-FL protein in CWR22Rv1 and VCaP cells is 2.12, 5.73, and 8.67 nM, and for AR-V protein, it is 4.72 and 0.29 nM. At 10 μM for 24 hours, ITRI-90 exhibits a prolonged duration of action across LNCaP, CWR22Rv1, and VCaP cells, allowing for reduced dosing frequency. Additionally, a 10 μM concentration for 6 or 10 hours in CWR22Rv1 cells results in AR protein degradation via the ubiquitin-proteasome pathway. However, at 0.1-1 μM for 24 hours, ITRI-90 shows low efficiency in inhibiting the expression of downstream target genes of AR and AR-V7 signaling pathways, as it mediates AR inhibition through degradation targeting the N-terminal domain or by blocking ligand binding in LNCaP and CWR22Rv1 cells. Administered at 0.001-100 μM for either 24 hours or 7 days, ITRI-90 selectively and effectively inhibits cancer cell proliferation and induces apoptosis in LNCaP, CWR22Rv1, and VCaP cells. Moreover, at 5 or 10 μM for 1-day treatment, ITRI-90 effectively degrades Enzalutamide-induced full-length AR and truncated AR V(ΔLBD) proteins in both short-term-treatment and long-term acquirer resistant cells, significantly weakening the growth of Enzalutamide-resistant VCaP, C4-2B, and C4-2B/EnzR cells. In mice liver microsomes, ITRI-90 exhibits a low plasma clearance rate (6.62 mL/min/kg) and a favorable actual in vivo exposure (AUC/dose = 2502.4).

Administered at 10 mg/kg via intraperitoneal injection twice daily for 15 days, ITRI-90 significantly suppresses tumor growth in the CWR22Rv1 xenograft mouse model, without evident toxicity during tumor regression. Additionally, ITRI-90, at 100 mg/kg, is an orally available degrader given twice daily for 21 days, specifically targeting full-length AR (AR-FL) and AR variants (AR-Vs) with truncated LBD domains during tumor regression in the same model.