MLN8237 is a selective Aurora A and Aurora B inhibitor with IC50 values of 1.2 and 396.5 nM, respectively. MLN8237 is at least 200-fold more selective for Aurora A (IC50= 6.7 nM) than Aurora B (IC50= 1.5 µM) according to cell-based assays. At a concentration of 50 nM MLN8237, cell-cycle analysis shows an increase in cells in the G2/M phase at 24 and 48 hours. At concentrations of 50 nM, 250 nM and 1 µM MLN8237, cell-cycle analysis also shows an increase in the number of cells with 8N DNA content. MLN8237 inhibits cell proliferation with IC50 values ranging from 15 to 469 nM in a broad panel of adherent and suspended cell lines.[1] HCT-116 cells with MLN8054 at 0.25, 1, and 4µM inhibits Aurora A autophosphorylation on T288. In mitotic HeLa cells, MLN8054 inhibits Aurora A in 1 hour with an average IC50 of 34 nM. In both HCT-116 colorectal and PC-3 prostate human tumor cells, treatment with 1 µM MLN8054 induces increased 4N cells relative to control cells. MLN8054 effectively inhibits the growth of various cell lines (HCT-116, SW480, DLD-1, MCF-7, MDA-MB-231, Calu-6, H460, SKOV-3 and PC-3) with IC50 values ranging from 0.11 to 1.43 µM.[2] In MM1.S and OPM1 MM cells, MLN8237 (0.5 µM) decreases phosphorylation of Aurora-A kinase. MLN8237 (0.1 nM-4 µM) induces inhibition of cell viability (40%-60%) and proliferation (70%-90%) in dexamethasone-resistant (MM.1R), melphalan-resistant (LR5), and doxorubicin-resistant (RPMI-DOX40) MM cells. Furthermore, costaining with annexin V and PI shows signi?cant induction of apoptosis by MLN8237 treatment (0.5-1 µM) in both MM cell lines (RPMI8226 and OPM1) and primary tumor cells as early as 24 hours. MLN8237 (0.5 µM) also induces cleavage of PARP, caspase 9, and caspase 3 in MM cell lines MM1S and OPM1.[3] In HCT-116 xenografts model, MLN8237 (orally at 3, 10, and 30 mg/kg) increases mitotic index, reduces bipolar mitotic spindles, and increases chromosome alignment abnormalities. In nude mice bearing subcutaneous HCT-116 tumors, MLN8237 treatment results in a dose-dependent tumor growth inhibition (TGI) of 43.3%, 84.2%, and 94.7% for the 3, 10, and 30 mg/kg groups, respectively. All doses of MLN8237 are well tolerated with the maximum body weight loss of 7.4% in the 30 mg/kg group. In the non-Hodgkin?? lymphoma model OCI-LY19, MLN8237 (either 20 mg/kg twice daily or 30 mg/kg once daily) results in a reduction in luminescent signal below baseline and a TGI of 106% for both groups. Moreover, tumors in the 20 mg/kg dose MLN8237 group do not grow back after more than 60 days of monitoring. Furthermore, MLN8237 shows broad antitumor activity across a diverse set of xenograft models, with TGI of greater than 76% at 30 mg/kg in all models tested.[1] |