Alrizomadlin (C09-1101-832)

Alrizomadlin (APG-115) is an orally active MDM2 protein inhibitor binding to MDM2 protein with IC 50 and K i values of 3.8 nM and 1 nM, respectively Alrizomadlin blocks the interaction of MDM2 and p53 and induces cell-cycle arrest and apoptosis in a p53-dependent mannerIn VitroAlrizomadlin (0.001-100 μM; 72 hours) inhibits cell proliferation in concentration-dependent manner, with IC 50 s of 18.9?±?15.6 nM and 103.5?±?18.3 nM respectively in AGS and MKN45 cells. ?/nAlrizomadlin (0.02 μM, 0.2 μM; 48 hours) enhances the anti-proliferative effect of radiotherapy at different radiation dose. ?/nAlrizomadlin (0.02 μM, 0.2 μM; 48 hours) affects progression by inducing cells arrested at G0/G1 phase in AGS and MKN45 cell with wild p53. ?/nAlrizomadlin (0.02 μM, 0.2 μM; 24 hours) activates p53 to enhance radiosensitivity in AGS and MKN45 cells; stable knockout of p53 abrogates expression of MDM2, p53, p21, PUMA, BAX, Cleaved-caspase3, γH2AX. ?/nAlrizomadlin (0.3 μM, 1 μM, 3 μM, 10 μM; 24 hours) leads to a concentration-dependent cell cycle arrest in G2/M phases and a decreasing in S-phase in p53 wide-type cell lines (TPC-1, KTC-1) . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: AGS and MKN45 cells Concentration: 0.0001 μM, 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, 100 μM Incubation Time: 72 hours Result: Inhibited cell proliferation in a concentration-dependent manner. RT-PCRCell Line: AGS and MKN45 cells Concentration: 0.02 μM, 0.2 μM Incubation Time: 48 hours Result: Elevated MDM2, p21, PUMA and BAX mRNA expression. Cell Cycle AnalysisCell Line: AGS and MKN45 cells Concentration: 0.02 μM, 0.2 μM Incubation Time: 48 hours Result: Arrested cells at G0/G1 phase. Apoptosis Analysis Cell Line: DePTC p53 wide-type cell line: TPC-1 cells, KTC-1 cells Concentration: 0.3μM, 1μM, 3μM, 10 μM Incubation Time: 24 hours Result: Reduced cell population in S-phase, whereas accumulation of cells at G2/M phases. Western Blot AnalysisCell Line: AGS and MKN45 cells Concentration: 0.2 μM Incubation Time: 72 hours Result: Enhanced expressions of MDM2 and p53, stable knockout of p53 abrogated them.In VivoAlrizomadlin (Delivered orally; 100 mg/kg; once daily; 10 days) enhances radiation antitumor effect in gastric adenocarcinoma in vivo. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Four-week-old male BALB/c athymic nude mice with MKN45 cellsDosage: 100 mg/kg Administration: Deliverer orally; once daily; 10 days Result: Decreased xenograft tumor growth.Form:SolidIC50& Target:IC50: 3.8 nm (APG-115). Specification: 0.98 Molecular Formula: C34H38Cl2FN3O4 Molecular Weight: 642.59 PubChem CID: 91972012 Isomeric SMILES: CCN1[C@H]([C@@H]([C@]2(C13CCCCC3)C4=C(C=C(C=C4)Cl)NC2=O)C5=C(C(=CC=C5)Cl)F)C(=O)NC67CCC(CC6)(CC7)C(=O)O