Characterization of novel diaryl oxazole-based compounds as potential agents to treat pancreatic cancer.
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 muM 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.
Shaw
Arthur Y
AY
College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Henderson
Meredith C
MC
Flynn
Gary
G
Samulitis
Betty
B
Han
Haiyong
H
Stratton
Steve P
SP
Chow
H-H Sherry
HH
Hurley
Laurence H
LH
Dorr
Robert T
RT
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D010080:Oxazoles; D000090063:Proto-Oncogene Mas; D016547:Kinesins