Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer

Arthur Y. Shaw, Meredith C. Henderson, Gary Flynn, Betty Samulitis, Haiyong Han, Steven P Stratton, Hsiao-Hui Chow, Laurence Hurley, Robert T Dorr

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 μM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.

Original languageEnglish (US)
Pages (from-to)636-647
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number2
DOIs
StatePublished - Nov 2009

Fingerprint

Oxazoles
Pancreatic Neoplasms
Kinesin
Cell Line
Protein Kinases
Interleukin-1 Receptor-Associated Kinases
Severe Combined Immunodeficiency
Proto-Oncogenes
Centromere
Receptor Protein-Tyrosine Kinases
Tumor Suppressor Genes
S Phase
Antineoplastic Agents
Action Potentials
Half-Life
Neoplasms
Cell Cycle
Necrosis

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer. / Shaw, Arthur Y.; Henderson, Meredith C.; Flynn, Gary; Samulitis, Betty; Han, Haiyong; Stratton, Steven P; Chow, Hsiao-Hui; Hurley, Laurence; Dorr, Robert T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 2, 11.2009, p. 636-647.

Research output: Contribution to journalArticle

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