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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1
Lynn Y L Huang1, Ying-Shuan Lee, Jiann-Jyh Huang
1Taivex Therapeutics Corporation, 17th Floor, No, 3, Yuanqu Street, Nangang District, Taipei City 115, Taiwan. lynnhuang.lh245@gmail.com.
Background:
Hec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in-class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility.
Methods:
The in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database.
Results:
TAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified.
Conclusions:
The excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti-cancer treatment regimens.
Insights
A new drug, TAI-1, targets the Hec1 protein overexpressed in cancers. TAI-1 shows potent anticancer effects in vitro and in vivo, with good safety and synergistic potential with other chemotherapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Hec1 (NDC80) is a kinetochore protein overexpressed in various human cancers.
- Hec1 is a promising molecular target for novel anticancer therapeutics.
Purpose of the Study:
- To characterize TAI-1, a first-in-class Hec1-targeting compound.
- To evaluate the potential of TAI-1 as an anticancer agent for clinical utility.
Main Methods:
- In vitro and in vivo studies assessed TAI-1's potency, specificity, synergy, and toxicity.
- Mechanism of action was confirmed via western blotting and immunofluorescence.
- Cardiac safety and clinical correlations were also evaluated.
Main Results:
- TAI-1 demonstrated broad-spectrum anticancer potency, disrupting Hec1-Nek2 interaction and inducing apoptosis.
- Effective oral administration in vivo was observed in triple-negative breast, colon, and liver cancer models.
- TAI-1 showed high specificity, no significant toxicity at efficacious doses, and synergistic effects with existing chemotherapies, with sensitivity linked to RB/P53 gene status.
Conclusions:
- TAI-1 exhibits potent anticancer activity, favorable safety, and synergistic potential.
- This Hec1-targeted small molecule demonstrates significant promise for clinical application in cancer treatment regimens.
