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Small molecules targeted to the microtubule-Hec1 interaction inhibit cancer cell growth through microtubule
M Ferrara1, G Sessa1, M Fiore1
1Institute of Molecular Biology and Pathology, CNR National Research Council, Rome, Italy.
Abstract:
Highly expressed in cancer protein 1 (Hec1) is a subunit of the kinetochore (KT)-associated Ndc80 complex, which ensures proper segregation of sister chromatids at mitosis by mediating the interaction between KTs and microtubules (MTs). HEC1 mRNA and protein are highly expressed in many malignancies as part of a signature of chromosome instability. These properties render Hec1 a promising molecular target for developing therapeutic drugs that exert their anticancer activities by producing massive chromosome aneuploidy. A virtual screening study aimed at identifying small molecules able to bind at the Hec1-MT interaction domain identified one positive hit compound and two analogs of the hit with high cytotoxic, pro-apoptotic and anti-mitotic activities. The most cytotoxic analog (SM15) was shown to produce chromosome segregation defects in cancer cells by inhibiting the correction of erroneous KT-MT interactions. Live cell imaging of treated cells demonstrated that mitotic arrest and segregation abnormalities lead to cell death through mitotic catastrophe and that cell death occurred also from interphase. Importantly, SM15 was shown to be more effective in inducing apoptotic cell death in cancer cells as compared to normal ones and effectively reduced tumor growth in a mouse xenograft model. Mechanistically, cold-induced MT depolymerization experiments demonstrated a hyper-stabilization of both mitotic and interphase MTs. Molecular dynamics simulations corroborate this finding by showing that SM15 can bind the MT surface independently from Hec1 and acts as a stabilizer of both MTs and KT-MT interactions. Overall, our studies represent a clear proof of principle that MT-Hec1-interacting compounds may represent novel powerful anticancer agents.
Insights
A novel compound, SM15, targets the Hec1-microtubule interaction, inducing chromosome instability and cancer cell death. This promising agent effectively reduces tumor growth with greater impact on cancer cells than normal cells.
Area of Science:
- Oncology
- Cell Biology
- Molecular Pharmacology
Background:
- Highly expressed in cancer protein 1 (Hec1) is crucial for chromosome segregation during mitosis.
- Hec1's overexpression in malignancies links it to chromosome instability and cancer progression.
- Hec1 represents a potential therapeutic target for novel anticancer drug development.
Purpose of the Study:
- To identify small molecules targeting the Hec1-microtubule interaction domain.
- To evaluate the anticancer potential of identified compounds, particularly their cytotoxic, pro-apoptotic, and anti-mitotic activities.
- To investigate the mechanism of action and in vivo efficacy of the most potent analog, SM15.
Main Methods:
- Virtual screening to identify compounds binding to the Hec1-microtubule interface.
- In vitro assays assessing cytotoxicity, apoptosis, and mitotic arrest in cancer cells.
- Live cell imaging to observe chromosome segregation and cell death.
- In vivo studies using a mouse xenograft model to evaluate tumor growth reduction.
- Cold-induced microtubule depolymerization assays and molecular dynamics simulations to elucidate mechanism.
Main Results:
- A virtual screen yielded a lead compound and analogs with significant cytotoxic, pro-apoptotic, and anti-mitotic effects.
- The analog SM15 induced chromosome segregation defects, mitotic arrest, and cell death (mitotic catastrophe) in cancer cells.
- SM15 demonstrated selective toxicity towards cancer cells over normal cells and reduced tumor growth in vivo.
- Mechanistic studies revealed SM15 hyper-stabilizes microtubules and KT-MT interactions, independent of Hec1 binding.
Conclusions:
- Compounds interacting with microtubule-Hec1 pathways are effective anticancer agents.
- SM15 represents a promising therapeutic candidate for cancer treatment due to its efficacy and selectivity.
- Targeting chromosome segregation machinery offers a viable strategy for novel anticancer drug discovery.
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