Second-Generation Antimitotics in Cancer Clinical Trials

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.

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

“…AZ82 43 ) have been shown to be effective in vitro ; however, their preclinical testing in cancer models is lacking. Inhibitors against Aurora kinases have already been clinically tested in solid tumors and hematologic malignancies; however, only poor or modest efficacy was observed, along with side-effects, such as neutropenia 13 . Alisertib (MLN8237) is the only Aurora A inhibitor progressed to Phase III evaluation in Peripheral T-Cell Lymphoma; however, no superior benefit was achieved over its investigator-selected single-agent comparator 44 .…”

“…However, in clinical settings, such mitosis-directed strategies have been unsuccessful with poor efficacy, potentially due to low fraction of mitotic cells within the tumors 11 . Furthermore, severe side effects associated with targeting of these proteins due to their multifaceted functions in several diverse processes 12,13 hinder their clinical development. Therefore, identifying and targeting novel proteins essential for both mitotic and non-mitotic cancer cells are necessary that will interfere with not only mitosis but also disrupt interphase-related processes to achieve long-lasting anti-tumorigenic effect with minimal toxicity 11 .…”

BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity

“…Antimitotic drugs, such as taxanes and vinca alkaloids, have been widely used in cancer therapy in recent years. However, there are some issues that need to be overcome, namely their side effects and the resistance mechanisms developed by cancer cells, motivating the need to discover new antimitotics [ 49 ]. Diarylpentanoids have been reported to exhibit antitumor activity by interfering with multiple biologic processes, including cell cycle [ 33 , 50 ].…”

BUB3, beyond the Simple Role of Partner

“…In turn, separase can cleave cohesins to promote sister chromatid separation (anaphase), while CDK1 inactivation promotes exit from mitosis. Reprinted from [ 23 ], MDPI 2021.…”