Abstract
Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA’s effectiveness. With the desire to overcome some of the MTA’s limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components.
Highlights
Academic Editor: Sanjay GargReceived: 24 May 2021Accepted: 29 June 2021Published: 2 July 2021Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.The cell cycle is a tightly regulated process in which a parental cell gives rise to two genetically identical daughter cells
The expression of polo-like kinase 1 (Plk1) was evaluated in 47.3% of patients, but the results demonstrated no relationship between Plk1 levels and Volasertib response
Better responses were achieved in patients with hematological tumors, especially against acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with Volasertib and Rigosertib, respectively, representing the most promising molecules among Plk1 inhibitors
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mitosis consists of five active phases: prophase, prometaphase, metaphase, anaphase, and telophase, followed by cytokinesis. MPS1 and Aurora B inhibition leads to SAC override, by massive chromosome missegregation and cell death. PLK1, Aurora A and Eg-5 inhibition induces spindle defects, while followed by massive chromosome missegregation and cell death. CENP-E inhibition promotes chromosome misalignment, leading to SAC activation, which in turn arrests cells in mitosis. Defects, while CENP-E inhibition promotes chromosome misalignment, leadingG1 toarrest/senescence, SAC activation, which in turn cycling. We will briefly discuss the current antimitotic approaches, and focus on the new generation of promising antimitotics that have reached clinical trials, with particular emphasis on their clinical efficacy These so-called second-generation antimitotics (SGAs) target the mitotic kinases and spindle motor proteins.
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