JPH203 (C09-0929-815)

InformationJPH203 JPH203 (KYT-0353, JPH-203SBECD), a selective L-type amino acid transporter 1 inhibitor, shows a dramatic inhibition of leucine uptake (IC50=0.06 µM) and cell growth (IC50=4.1 µM) in human colon cancer cells (HT-29), human oral cancer cells (YD-38) and leukemic cells.TargetsLAT1 (Cell-free assay)In vitroJPH203 completely and slightly inhibited the L-Leucine uptake in YD-38 cells (IC50 value: 0.79 μM) and NHOKs (IC50 value: >100 μM), respectively. JPH203 inhibited HT-29 cell growth, generating an apparent IC50 of 4.1 μM, but the JPH203 IC50 concentration (0.06 μM) needed to inhibit the L-Leucine uptake did not inhibit HT-29 cell growth, which represents a 68-fold difference in susceptibility. JPH203 activated the mitochondria-dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bad, Bax, and Bak, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl-2 and Bcl-xL in Saos2 human osteosarcoma cells. JPH203 can distinguish relative abundance between LAT1 and LAT2. It has high selectivity for LAT1. JPH203 was metabolically stable in mouse, rat, dog, monkey and human liver microsomal incubations. JPH203 induces both G2/M and G0/G1 cell cycle arrest, as well as reduced the S phase accompanied by altered expression of the proteins in cell cycle progression: cyclin D1, CDK4, and CDK6.In vivoDaily intravenous administration of JPH203 (12.5 and 25 mg/kg) significantly inhibited tumor growth in KKU-213 cholangiocarcinoma cell xenografts in the nude mice model in a dose-dependent manner with no statistically significant change in the animal’s body weight and with no differences in the histology and appearance of the internal organs compared with the control group. Thus, JPH203 shows anti-tumor efficacy in nude mice bearing human cholangiocarcinom (CCA) cell xenografts without general toxicity.Cell Research(from reference)Cell lines：Saos2 human osteosarcoma cells Concentrations：100 µM Incubation Time：72 h. Specification: 0.97 Molecular Formula: C23H19Cl2N3O4 Molecular Weight: 472.32 PubChem CID: 24853505 Isomeric SMILES: C1=CC=C(C=C1)C2=NC3=CC(=CC(=C3O2)COC4=C(C=C(C=C4Cl)C[C@@H](C(=O)O)N)Cl)N