Genetic instability, a hallmark feature of cancer, often arises from chromosome segregation errors during mitosis in part due to deregulation of certain cancer-associated genes. Over the past decade, Hec1 (Highly Expressed in Cancer 1), originally discovered by us in 1997, has been increasingly recognized as a key regulator in mitotic processes including kinetochore-microtubule attachment, Mad2-dependent spindle assembly checkpoint activation and spindle assembly. Importantly, overexpression of Hec1 associates with poor prognosis of primary breast cancers in human and is also found to initiate tumor formation in a mouse model, thus stipulating Hec1 as an oncogene. Recent work from our lab has shown that targeting the Hec1/Nek2 mitotic pathway with a small molecule INH1 efficiently retards the breast cancer cell growth in culture and in animals, demonstrating that Hec1 may serve as a novel molecular target for cancer intervention. In this application, we propose to refine and optimize the lead compound INH1 to generate analogues feasible for potential clinical application as well as to elucidate the detailed molecular and cellular mechanism of how the INH1 inhibitor works. Two major specific aims are proposed in this application: first is to design, synthesize, and biologically evaluate the second and third generations of INH1 analogues;second is to elucidate molecular and cellular mechanisms of the most active INH analogues. We are in an excellent position to further generate derivatives with nanomolar potency and to dissect the detailed mode-of-action of INH compounds. Accomplishing the objectives outlined in this study will represent an important milestone toward the translation of this potential drug into clinical application.

Public Health Relevance

Hec1 is recognized for its critical roles in a variety of mitotic processes and serves as an oncogene. We have identified a small molecule INH1 which retards the breast cancer cell growth by targeting the Hec1/Nek2 mitotic pathway, demonstrating that Hec1 can serve as a novel molecular target for cancer intervention. We proposed here to generate INH1 analogues with nanomolar potency and to dissect the detailed mode-of-action of these INH compounds. Accomplishing the objectives outlined in this proposal will represent an important milestone toward the translation of this potential drug into clinical application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107568-26
Application #
8451599
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Hildesheim, Jeffrey
Project Start
1991-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
26
Fiscal Year
2013
Total Cost
$334,456
Indirect Cost
$115,857
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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