Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

Abstract

Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure−activity relationships, and future directions of dual-target tubulin inhibitors.

Synthesis and evaluation of 2‐aryl‐1 H ‐benzo[d]imidazole derivatives as potential microtubule targeting agents

“…Development of the anticancer drugs that can selectively target cancer cells has remained a significant research area for decades (Mould & Hutson, 2017; Paul et al, 2010). Microtubules are composed primarily of α and β‐tubulin heterodimers, and they are the targets for developing novel anticancer drugs (Jordan & Wilson, 2004; Muhlethaler et al, 2021; Shuai et al, 2021). Microtubule is crucial for the normal functioning of cells, including maintenance of cell morphology and motility, intracellular trafficking of cellular components, and most importantly, cell division (Bornens, 2012; Kueh & Mitchison, 2009).…”

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

“…[ 2 ] CA‐4 interacts with the colchicine binding site of tubulin, and during the past decades, several of its analogs were synthesized and tested in vitro and in vivo. [ 1–3 ] Many of these analogs were obtained by isosteric replacement of double bond and/or aromatic rings with aromatic heterocycles, including pyrrole, imidazole, isoxazole, and so forth, aiming to improve the activity, stability, pharmacokinetic properties, and toxicological profile of the lead molecule. [ 1–3 ] The choice of certain heterocycles in such replacements was driven both by their physicochemical characteristics and their synthetic accessibility.…”

“…[ 1–3 ] Many of these analogs were obtained by isosteric replacement of double bond and/or aromatic rings with aromatic heterocycles, including pyrrole, imidazole, isoxazole, and so forth, aiming to improve the activity, stability, pharmacokinetic properties, and toxicological profile of the lead molecule. [ 1–3 ] The choice of certain heterocycles in such replacements was driven both by their physicochemical characteristics and their synthetic accessibility. However, although the binding sites and the basic mechanisms of action of these compounds are apparently similar, they may show substantial differences in the activity levels and diverse influences on the cell cycle and MT network morphology, [ 4 ] and the factors affecting these effects are not yet fully understood.…”

Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation

“…However, rational molecular design of dual tubulin/PARP-1 inhibitors for cancer therapy still presents great challenges. To date, few dual-targeting inhibitors targeting both tubulin and PARP-1 have been reported. , …”

“…To date, few dual-targeting inhibitors targeting both tubulin and PARP-1 have been reported. 70,71 Docking-based virtual screening has become a valuable in silico technique that has great potential to identify novel active compounds in the pharmaceutical industry alongside traditional high-throughput screening. 72−74 Structure-based pharmacophore models provide an efficient alternative to dockingbased virtual screening of small molecules and their combined screening can effectively improve the identification efficiency of lead compounds.…”