Cyclin-dependent kinase inhibitor, P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription

P276-00 is a novel cyclin-dependent kinase inhibitor especially potent for Cdk9-T1, Cdk4-D1 and Cdk1-B. Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of malignant plasma cells. Treatment of MM cell lines with P276-00 resulted in apoptosis that correlated with transcription inhibition and a significant decline in Mcl-1 protein levels with the appearance of cleaved PARP in these cells. In vivo studies of P276-00 confirmed antitumor activity in RPMI-8226 xenograft. These results suggest that P276-00 causes multiple myeloma cell death by disrupting the balance between cell survival and apoptosis through inhibition of transcription and downregulation of Mcl-1. (C) 2010 Elsevier Ltd. All rights reserved.