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

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Summary

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.

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Acknowledgments

This work was supported by grants PO1 CA109552 (DD Von Hoff) and P30 CA23074 from the National Cancer Institute, National Institutes of Health, Bethesda MD, USA. We would like to thank Vijay Gokhale, PhD., for synthesis and validation of PC-046. We would like to acknowledge the following University of Arizona Cancer Center core services: Flow Cytometry, Analytical Core, Experimental Mouse Shared Service, and the Biostatistical Core, and the University of Arizona Genetics Core for their services. The NCI-60 screening and COMPARE analysis was performed by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute.

Conflicts of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. The University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA

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

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  1. Terry H. Landowski
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  2. Betty K. Samulitis
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  3. Robert T. Dorr
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Correspondence to Robert T. Dorr.

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Supplemental Fig. 1

Distribution of PC-046 in (a) plasma or (b) bone marrow after a single 100 mg/kg dose by the IP route. Total bone marrow PC-046 concentration is presented (combined right and left bone marrow flushings). Results shown are mean (SEM), n = 4 (JPEG 49 kb)

High resolution image (TIFF 105 kb)

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Landowski, T.H., Samulitis, B.K. & Dorr, R.T. The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers. Invest New Drugs 31, 1616–1625 (2013). https://doi.org/10.1007/s10637-013-0019-8

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  • DOI: https://doi.org/10.1007/s10637-013-0019-8

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