The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers

Terry H. Landowski, Betty K. Samulitis, Robert T. Dorr

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Microtubule targeting agents are among the most widely used chemotherapeutics for both solid and hematological malignancies. This study characterizes the diaryl-oxazole based anticancer agent PC-046, which was originally identified for development based on selective activity in deleted in pancreas cancer locus 4 (DPC4/SMAD4) deficient tumors. PC-046 has growth inhibitory activity in a variety of tumor types in vitro, and efficacy in SCID mice was shown in human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma, and DU-145 prostate cancer. Pharmacokinetic studies demonstrated relatively high oral bioavailability (71 %) with distribution to both plasma and bone marrow. No myelosuppression was seen in non-tumor bearing SCID mice given a single dose just under the acute lethal dose. The COMPARE algorithm in the NCI-60 cell line panel demonstrated that PC-046 closely correlated to other known tubulin destabilizing agents (correlation coefficients ≈0.7 for vincristine and vinblastine). Mechanism of action studies showed cell cycle arrest in metaphase and inhibition of tubulin polymerization. Overall, these studies show that PC-046 is a synthetically-derived, small molecule microtubule destabilizing agent. Advantages over existing microtubule destabilizing agents include ease of synthesis, lack of MDR cross-resistance, good oral bioavailability and the lack of acute myelotoxicity.

Original languageEnglish (US)
Pages (from-to)1616-1625
Number of pages10
JournalInvestigational New Drugs
Volume31
Issue number6
DOIs
StatePublished - Dec 2013

Keywords

  • Diaryl oxazole
  • Metaphase arrest
  • Microtubule inhibitor
  • PC-046

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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