Microtubule-Targeting Agents: Advances in Tubulin Binding and Small Molecule Therapy for Gliomas and Neurodegenerative Diseases

Abstract

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer's and Parkinson's. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood-brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets-including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites-that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody-drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases.

Keywords: cancer; cytoskeleton; neurodegeneration; tubulin.

Figure 1

Microtubule structure and dynamics. (A) Cytoskeleton components and microtubule structure. The cell cytoskeleton is composed of actin (red), intermediate filaments (purple), and microtubules (green). Tubulin heterodimers consisting of α- (light green) and β-subunits (dark green) assemble into protofilaments. Thirteen protofilaments further polymerize to form a hollow cylinder about 25 nm in diameter. (B) Structural dynamics of microtubules. The γ-tubulin ring complex is the starting point for microtubule nucleation. Growing microtubules favour assembly at the plus end (left to right) versus shrinking towards the minus end (right to left). The plus end exposes the β-tubulin, and the minus end exposes the α-tubulin. Created with BioRender.com (accessed 25 June 2025).

Figure 2

Binding sites of Microtubule-Targeting Agents (MTAs). Nine MTA binding sites of tubulin. Two tubulin heterodimers (α-subunits, light grey; β-subunits, grey). The representative agents bound to the nine sites are shown in colour: maytansine site (yellow, PDB ID 4TV8); tumabulin site (cyan, PDB ID 7CEK); gatorbulin site (blue, PDB ID 7ALR); colchicine site (green, PDB ID 4O2B); pironetin site (purple, PDB ID 5LA6); todalam site (black, PDB ID 7Z7D); vinca site (vinblastine, orange, PDB ID 5J2T); peloruside A/laulimalide site (pink, PDB ID 4O4J); and taxane site (paclitaxel, red, PDB ID 6WVR). Schematic made with ChimeraX (version 1.10rc202506232245).

Figure 3

Summary of Microtubule-Targeting Agents. Microtubule-Destabilizing Agents (MDAs) [left]. Chemical structures of representative MDAs. MDAs aim to destabilize microtubules, leading to impaired structural integrity and inhibiting the tubulin polymerization into microtubules. RGN3067 (yellow), PTC596 (blue), Pironetin (pink), ST-401 (black), Vinblastine (green), Vinorelbine (red), Vincristine (teal), Tumabulin-1 (purple), Tumabulin-2 (dark pink), and 4AZA2891 (brown). Microtubule-Stabilizing Agents (MSAs) [right]. Chemical structures of representative MSAs. MSAs aim to stabilize microtubules, promoting the polymerization of purified tubulin and enhancing microtubule density. Taxol (black), Docetaxel (blue), Cabazitaxel (pink), TPI-287 (purple), Epothilone B (green), Epothilone D (teal), Laulimalide (orange), Peloruside A (yellow), and Sagopilone (red). Structures built with MolView (v4.10.0). Created with BioRender.com (accessed 25 June 2025).