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UA62784, a novel inhibitor of centromere protein E kinesin-like protein

Meredith C Henderson1, Yeng-Jeng Y Shaw, Hong Wang

  • 1Arizona Cancer Center, BIO5 Institute, College of Pharmacy, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA.

Molecular Cancer Therapeutics
|January 14, 2009
PubMed

Insights

A novel compound, UA62784, inhibits centromere protein E (CENP-E) to arrest mitosis in pancreatic cancer cells. This finding suggests a potential new therapeutic strategy for pancreatic carcinoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Pancreatic carcinoma is a leading cause of cancer-related mortality.
  • There is a critical need for novel therapeutic targets and treatment options for pancreatic cancer.
  • Centromere protein E (CENP-E) is a kinesin-like protein crucial for mitosis.

Purpose of the Study:

  • To identify and characterize novel compounds with inhibitory activity against pancreatic carcinoma cells.
  • To investigate the mechanism of action of the novel fluorenone compound UA62784.
  • To evaluate the potential of UA62784 as a therapeutic agent for pancreatic cancer.

Main Methods:

  • Isolation and screening of compounds in isogenic pancreatic carcinoma cell lines.
  • Assay of UA62784's inhibitory activity against CENP-E.
  • Analysis of UA62784's effect on mitotic progression and chromosome congression.
  • Investigation of UA62784's binding interaction with CENP-E.

Main Results:

  • UA62784, a novel fluorenone, was isolated and found to be selective in DPC4-deleted pancreatic carcinoma cell lines.
  • UA62784 inhibits CENP-E's microtubule-associated ATPase activity, causing mitotic arrest.
  • The compound inhibits chromosome congression at the metaphase plate.
  • UA62784 does not affect CENP-E binding to kinetochores, indicating interaction with the motor domain.

Conclusions:

  • UA62784 is a novel and specific inhibitor of CENP-E.
  • The mechanism involves disruption of CENP-E motor function, leading to mitotic arrest.
  • UA62784 demonstrates potential as a novel antimitotic drug for treating pancreatic carcinomas.

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