Small Molecules Targeted to the Microtubule-Hec1 Interaction Inhibit Cancer Cell Growth through Microtubule Stabilization

Ferrara M, et al, 37(2):231-240, Oncogene, 2018

Highly expressed in cancer protein 1 (Hec1) is a component of the kinetochore (KT)-associated Ndc80 complex. Hec1 plays an important role in the binding of microtubules (MTs) to the KT during mitotic division. Hec1 is considered a promising molecular target for developing new therapeutic drugs against cancer cell growth. Described herein is an in silico virtual screening of the SPECS library of commercially available compounds to identify small molecules (SMs) that are capable of binding at the interaction domain between MTs and Hec1. One promising hit compound (SM15) and an analog of the initial hit was identified. The kinetics and affinity of the binding between proteins (tubulin and assembled MTs) and SMs were evaluated by surface plasmon resonance (SPR) using a Pall ForteBio Pioneer system. Ligands (tubulin and assembled MTs) were immobilized onto activated COOH5 sensor chips via standard amine coupling chemistry. Any residual active sites were blocked by injecting ethanolamine hydrochloride. Subsequently, SM15 samples at different concentrations were injected in duplicates over the sensor chip. The sensor chip surface was regenerated by injecting glycine (pH 1.5). KD values were determined for the SM15 interactions with MTs and tubulin. Collectively, the results of this study provide evidence to support MT-Hec1-interacting compounds as promising anticancer agents.

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