JR4-187

JR4-187 is an orally active copper-dependent anti-cancer agent. It downregulates genes involved in oxidative phosphorylation, MYC targets, and E2F targets, while upregulating genes associated with the TNF-α signaling pathway, p53 pathway, and KRAS signaling pathway, in addition to reducing CTR1 protein levels. JR4-187 induces ROS production, apoptosis (apoptosis), and copper-dependent cytotoxicity, with selective cytotoxicity towards KRAS mutant cancer cells. It exhibits good tolerability in pancreatic cancer mouse models. JR4-187 is applicable for research in pancreatic ductal adenocarcinoma, colon cancer, rectal cancer, and other related cancers.

JR4-187 at 2 μM for 24 hours can downregulate genes associated with oxidative phosphorylation, MYC targets, and E2F targets in HCT116 cells while upregulating genes involved in TNF-α signaling, the p53 pathway, and KRAS signaling. At concentrations of 2.5-15 μM for 4-24 hours, JR4-187 significantly reduces the expression of MYC and NDUFS7 proteins in HCT116, MIA PaCa-2, PANC1, and BxPC3 cells. When combined with specific compounds like Danazol and Metformin, JR4-187 (0.03-1 μM; 6 days) shows a synergistic cytotoxic effect in HCT116 colon cancer cells, and an antagonistic effect when combined with compounds such as MYCi361 and 10058-F4. At 10 μM for 24 hours, it notably decreases CTR1 protein expression in HCT116 and MIA PaCa-2 cells. A combination of JR4-187 at 2.5 μM with 5 μM AGB-374 synergistically downregulates MYC and NDUFS7 protein expression in HCT116 cells. Known as Compound 39, JR4-187 strongly inhibits the proliferation of KRAS-mutant pancreatic and colon cancer cells, exhibiting high activity in SU.86.86 cells (IC 50 = 0.8 μM) and MIA PaCa-2 cells (IC 50 = 1.9 μM), with lower activity in KRAS wild-type BxPC-3 cells. JR4-187 (0-10 μM; 6 days) has copper-dependent cytotoxicity, showing strong synergy with CuSO4 in MIA PaCa-2 and HCT116 cells, and its activity decreases in the presence of the copper chelator TTM. At 0-5 μM for 6 days, it exhibits strong synergy with COX2 inhibitors Celecoxib and Rofecoxib in inhibiting colony formation in HCT116, MIA PaCa-2, and BxPC-3 cells. At 0-1 μM for 6 days, JR4-187 induces ROS-dependent cell death in HCT116 and MIA PaCa-2 cells and partially induces cell death via apoptosis and necroptosis at concentrations of 0-10 μM over 1-6 days.

JR4-187 (20-40 mg/kg; intraperitoneal injection; daily; days 1-28) demonstrates good tolerability in female C57BL/6 mice with PAN02 pancreatic cancer allografts.