Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

Leukemia. 2009 May;23(5):961-70. doi: 10.1038/leu.2008.378. Epub 2009 Jan 8.


Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Blotting, Western
  • Bone Marrow / drug effects
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Caspases / metabolism
  • Cell Adhesion / drug effects
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cyclin D1 / antagonists & inhibitors*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor Proteins / antagonists & inhibitors
  • Down-Regulation
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Flavones / therapeutic use*
  • Gene Expression Profiling
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, SCID
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / pathology
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation / drug effects
  • Pyrazines / therapeutic use
  • Retinoblastoma Protein / metabolism
  • Stromal Cells / drug effects
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Boronic Acids
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Flavones
  • Interleukin-6
  • P276-00
  • Pyrazines
  • Retinoblastoma Protein
  • Cyclin D1
  • Insulin-Like Growth Factor I
  • Bortezomib
  • Caspases