Microtubule‐targeting agents for cancer treatment: Seven binding sites and three strategies

Abstract

Microtubules are pivotal in diverse cellular functions encompassing cell signaling, morphology, intracellular trafficking, and cell mitosis/division. They are validated targets for disease treatment, notably hematological cancers and solid tumors. Microtubule‐targeting agents (MTAs) exert their effects by modulating microtubule dynamics, impeding cell proliferation, and promoting cell death. Recent advances in structural biology have unveiled novel perspectives for investigating multiple binding sites and mechanisms of action used by MTAs. In this review, we first provide an overview of the intricate structure and dynamics of microtubules. Then we explore the seven binding sites and the three primary strategies (stabilization, destabilization, and degradation) harnessed by MTAs. Furthermore, we introduce the emerging domain of microtubule‐targeting degraders, exemplified by PROteolysis TArgeting Chimeras and small‐molecule degraders, which enable precise degradation of specific microtubule‐associated proteins implicated in cancer pathogenesis. Additionally, we discuss the promising realm of precision‐targeted approaches, including antibody–drug conjugates and the utilization of photopharmacology in MTAs. Lastly, we provide a comprehensive overview of the clinical applications of microtubule‐targeting therapies, assessing their efficacy and current challenges. We aim to provide a global picture of MTAs development as well as insights into the microtubule‐targeting drug discovery for cancer treatment.

Synthesis, characterization of novel N‐(4‐cyano‐1,3‐oxazol‐5‐yl)sulfonamide derivatives and in vitro screening their activity against NCI‐60 cancer cell lines

“…[11] COMPARE analysis of the results obtained in the in vitro one-dose experiment showed a moderate correlation of the tested compounds across vectors reflecting antiproliferative activity with those of the L-cysteine analog and vinblastine (GI 50 ), as well as paclitaxel (TGI), targeted microtubules. [12][13][14] Analysis of the results obtained in the five-dose experiment showed a similar correlation of the GI 50 vectors of compounds 2 and 10 with L-cysteine and maytansine, respectively, the latter also targeting microtubules. [15,16] Therefore, disruption of microtubule formation may be one mechanism for the tested compounds' anticancer activity.…”

BP-M345 as a Basis for the Discovery of New Diarylpentanoids with Promising Antimitotic Activity

“…3,5-bis(3,4,5-trimethoxybenzyl)tetrahydro-4H-pyran-4-one (10). Yield: 24.3% as yellow gum; 99.9% purity; 1 H NMR (CDCl 3 , 400.14 MHz) δ: 6.37 (s, 4H, H-2 ′ , -6 ′ ), 4.18 (q, J = 5.8 Hz,…”

“…The solvent was evaporated under reduced pressure. A mixture of products was obtained and purified by flash CC (SiO 2 ; n-hexane: ethyl acetate, 4:6) and preparative TLC (SiO 2 ; n-hexane:ethyl acetate, 3:7) to give a yellow gum corresponding to 3,5-bis(3,4,5-trimethoxybenzyl)tetrahydro-4H-pyran-4-one (10).…”

“…Such perturbation is accomplished by microtubule-targeting agents (MTAs), the best characterized therapeutic drugs for the treatment of a wide range of tumor types [1][2][3][4][5][6][7]. MTAs consist of microtubule destabilizers such as vinca alkaloids (e.g., vinblastine and vincristine) and microtubule stabilizers such as taxanes (e.g., paclitaxel and docetaxel) [8][9][10][11][12][13]. Microtubule destabilizers inhibit microtubule polymerization through binding to tubulin dimers, while microtubule stabilizers inhibit microtubule dynamics through binding to tubulin polymers [14,15].…”

Design, synthesis and cytotoxic activity of molecular hybrids based on quinolin-8-yloxy and cinnamide hybrids and their apoptosis inducing property

“…5 In recent times, tubulin polymerization has been recognized as a signicant molecular target for the search and development of anticancer drugs. 6 The polymerization of tubulin is necessary to form microtubules that have a crucial role in cellular functions, including the maintenance of cellular structure, intracellular transportation as well as mitotic spindle formation for cell division. 7,8 In recent decades, a wide range of natural compounds and synthetic components have been identied as anticancer drugs that interfere with tubulin-microtubule dynamics.…”