Background:

JK184 is a potent Hedgehog (Hh) pathway inhibitor with IC50 of 30 nM in mammalian cells.

JK184 is designed to antagonize Hh signaling by inhibiting glioma (Gli)-dependent transcriptional activity in a dose dependent manner. JK184 significantly inhibitts proliferation of HUVECs with IC50 of 6.3 μg/mL after three days incubation. To evaluate anti-tumor effect of JK184, MTT assay is conducted in Panc-1 and BxPC-3 cells after administration with indicated concentrations of compounds, half maximal inhibitory concentration (IC50) of JK184 (23.7 ng/mL in anc-1 and 34.3 ng/mL in BxPC-3)[1]. Claudin-low cell lines are more sensitive to JK184 treatment than are MCF10a, MTSV1-7, or HMLE-shGFP and HMLE-pBP cells, and JK184 induced a dose-dependent decrease in glioma-associated oncogene homolog 1 (GLI1) transcript and protein levels in these cells. Treatment with the IC50 dose of JK184 enhances the proportion of HMLE-shEcad cells that stained with Annexin-V, but are negative for propidium iodide (PI) (P<0.0001, t test)[2].

JK184 (5 mg/kg, injected intravenously) exhibits good anti-proliferative activity in subcutaneous Panc-1 and BxPC-3 tumor models, and is a good candidate as antitumor drug targeted Hh signaling. However, JK184 has a poor pharmacokinetic profile and bioavailability[1].

参考文献:
[1]. Zhang N, et al. Biodegradable polymeric micelles encapsulated JK184 suppress tumor growth through inhibiting Hedgehog signaling pathway. Nanoscale. 2015 Feb 14;7(6):2609-24.
[2]. Colavito SA, et al. Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. Breast Cancer Res. 2014 Sep 25;16(5):444.