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

3 Citations (Scopus)

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

Fingerprint

Oxazoles
Tubulin
Microtubules
SCID Mice
Biological Availability
Neoplasms
Vinblastine
Vincristine
Hematologic Neoplasms
Metaphase
Cell Cycle Checkpoints
Multiple Myeloma
Pancreatic Neoplasms
Heterografts
Acute Myeloid Leukemia
Polymerization
Antineoplastic Agents
Prostatic Neoplasms
Pharmacokinetics
Bone Marrow

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers. / Landowski, Terry H; Samulitis, Betty K.; Dorr, Robert T.

In: Investigational New Drugs, Vol. 31, No. 6, 12.2013, p. 1616-1625.

Research output: Contribution to journalArticle

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