YZ-836P

YZ-836P is a Protein arginine methyltransferase 5 ( PRMT5 ) targeting agent. YZ-836P promotes ubiquitination and proteasomal degradation of PRMT5 in a cereblon ( CRBN )-dependent manner, which in turn reduces levels of its downstream target KLF5. YZ-836P induces G1 phase cell cycle arrest in triple-negative breast cancer cells. YZ-836P induces Apoptosis in triple-negative breast cancer cells. YZ-836P exerts cytotoxic effects on triple-negative breast cancer cells. YZ-836P inhibits the growth of triple-negative breast cancer patient-derived organoids. YZ-836P inhibits the growth of triple-negative breast cancer xenografts in nude mice. YZ-836P can be used for the research of triple-negative breast cancer ^[1]. (Pink: PRMT5 ligand; Blue: Cereblon ligand; Black: linker).

In Vivo, YZ-836P (50 mg/kg; i.p.; every other day; 4 total doses) exerts potent in vivo anti-tumor activity against TNBC xenografts, reducing tumor growth without inducing measurable systemic toxicity^[1].

In Vitro, YZ-836P (0-6 µM; 48 h) potently reduces cell viability in HCC1806 (IC₅₀ = 2.1 µM) and HCC1937 (IC₅₀ = 1.0 µM) TNBC cell lines after 48 h treatment^[1]. YZ-836P (0-10 µM; 48 h) and (4 µM; 0-72 h) dose-dependently and time-dependently reduces PRMT5 and KLF5 protein levels in HCC1806 and HCC1937 TNBC cell lines^[1]. YZ-836P (0.25-1.00 µM; 2 days) concentration-dependently inhibits colony formation in HCC1806 and HCC1937 TNBC cell lines when applied for an initial 2-day treatment^[1]. YZ-836P (1-6 µM; 24 h) concentration-dependently inhibits DNA synthesis in HCC1806 and HCC1937 TNBC cell lines after 24 h treatment^[1]. YZ-836P (2-6 µM; 48 h) concentration-dependently induces G1 phase cell cycle arrest in HCC1806 and HCC1937 TNBC cell lines after 48 h treatment^[1]. YZ-836P (2-6 µM; 48 h) concentration-dependently modulates cell cycle-related protein expression (reduces Cyclin D1, CDK4, CDK6; increases p21, p27) in HCC1806 and HCC1937 TNBC cell lines after 48 h treatment^[1]. YZ-836P (2-6 µM; 48 h) concentration-dependently modulates apoptosis-related protein expression (increases cleaved PARP, cleaved Caspase 3; reduces XIAP, Mcl-1) in HCC1806 and HCC1937 TNBC cell lines after 48 h treatment^[1]. YZ-836P (2-6 µM; 48 h) concentration-dependently induces apoptosis in HCC1806 and HCC1937 TNBC cell lines after 48 h treatment^[1]. YZ-836P (4 µM) directly binds to PRMT5, increasing its thermostability (CETSA assay) and reducing its susceptibility to protease degradation (DARTS assay) in HCC1806 and HCC1937 TNBC cell lines^[1]. YZ-836P (4 µM; 48 h) increases PRMT5 ubiquitination and promotes CRBN-dependent, proteasomal-mediated degradation of PRMT5 in HEK293T cells^[1]. YZ-836P (0-10 µM; 48 h) potently reduces viability of TNBC patient-derived organoids PDO-32 (IC₅₀ = 2.072 µM) and PDO-33 (IC₅₀ = 4.746 µM) after 48 h treatment^[1].

References:
[1]. Guo Y, et al. Targeting PRMT5 through PROTAC for the treatment of triple-negative breast cancer. J Exp Clin Cancer Res. 2024;43(1):314. Published 2024 Nov 30.