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.
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.
|Hu, C-M; Zhu, J; Guo, X E et al. (2015) Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism. Oncogene 34:1220-30|
|Zhu, Jiewen; Chen, Hongyuan; Guo, Xuning Emily et al. (2015) Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors. Eur J Med Chem 96:196-208|
|Guo, Xuning Emily; Ngo, Bryan; Modrek, Aram Sandaldjian et al. (2014) Targeting tumor suppressor networks for cancer therapeutics. Curr Drug Targets 15:2-16|
|Ngo, Bryan; Hu, Chun-Mei; Guo, Xuning Emily et al. (2013) Complementary interhelical interactions between three buried Glu-Lys pairs within three heptad repeats are essential for Hec1-Nuf2 heterodimerization and mitotic progression. J Biol Chem 288:34403-13|
|Wei, Randy; Ngo, Bryan; Wu, Guikai et al. (2011) Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint. Mol Biol Cell 22:3584-94|
|Tsai, Connie Y; Ngo, Bryan; Tapadia, Anjali et al. (2011) Aurora-A phosphorylates Augmin complex component Hice1 protein at an N-terminal serine/threonine cluster to modulate its microtubule binding activity during spindle assembly. J Biol Chem 286:30097-106|
|Lin, Li-Fang; Chuang, Chih-Hung; Li, Chien-Feng et al. (2010) ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer. Cancer Res 70:192-201|
|Qiu, Xiao-Long; Li, Guideng; Wu, Guikai et al. (2009) Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues. J Med Chem 52:1757-67|
|Wu, Guikai; Wei, Randy; Cheng, Eric et al. (2009) Hec1 contributes to mitotic centrosomal microtubule growth for proper spindle assembly through interaction with Hice1. Mol Biol Cell 20:4686-95|
|Wu, Guikai; Qiu, Xiao-Long; Zhou, Longen et al. (2008) Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res 68:8393-9|
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