title: The diaryl oxazole PC-046 is a tubulin-binding agent with experimental anti-tumor efficacy in hematologic cancers.
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.
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA, tlandowski@uacc.arizona.edu.
authors.forename: Terry H
authors.initials: TH
authors.lastname: Landowski
authors.forename: Betty K
authors.initials: BK
authors.lastname: Samulitis
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dorr
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000589328:5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl)oxazole; D000970:Antineoplastic Agents; D010080:Oxazoles; D011725:Pyridines; D014404:Tubulin; D050257:Tubulin Modulators; D020169:Caspases
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