Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives have been synthesized and evaluated for their anticancer potential against various cancer cell lines. Structure–activity relationship studies have shown that appropriate substitution on different positions of the pyrazole ring can significantly enhance anticancer efficacy and tumor selectivity. It is noteworthy that many pyrazole derivatives have demonstrated multiple mechanisms of anticancer action by interacting with various targets including tubulin, EGFR, CDK, BTK, and DNA. Therefore, this review summarizes the current understanding on the structural features of pyrazole derivatives and their structure-activity relationships with different targets, aiming to facilitate the development of potential pyrazole-based anticancer drugs. We focus on the latest research advances in anticancer activities of pyrazole compounds reported from 2018 to present.

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC50 value of 0.011 μM. Furthermore, the IC50 values of compound MY-413 was less than 0.1 μM for other 17 cancer cell lines and less than 0.05 μM for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC50 = 2.46 μM) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent. 

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities.

Microtubules are a well-known target in cancer chemotherapy because of their critical role in cell division. Chromosome segregation during mitosis depends on the establishment of the mitotic spindle apparatus through microtubule dynamics. The disruption of microtubule dynamics through the stabilization or destabilization of microtubules results in the mitotic arrest of the cells. Microtubule-targeted drugs, which interfere with microtubule dynamics, inhibit the growth of cells at the mitotic phase and induce apoptotic cell death. The principle of microtubule-targeted drugs is to arrest the cells at mitosis and reduce their growth because cancer is a disease of unchecked cell proliferation. Many anti-microtubule agents produce significant inhibition of cancer cell growth and are widely used as chemotherapeutic drugs for the treatment of cancer. The drugs that interact with microtubules generally bind at one of the three sites vinblastine site, taxol site, or colchicine site. Colchicine binds to the interface of tubulin heterodimer and induces the depolymerization of microtubules. The colchicine binding site on microtubules is a much sought-after target in the history of anti-microtubule drug discovery. Many colchicine-binding site inhibitors have been discovered, but their use in the treatment of cancer is limited due to their dose-limiting toxicity and resistance in humans. Combination therapy can be a new treatment strategy to overcome these drawbacks of currently available microtubule-targeted anticancer drugs. This review discusses the significance of microtubules as a potential pharmacological target for cancer and stresses the necessity of finding new microtubule inhibitors to fight the disease. 

Microtubules and Cell Division: Potential Pharmacological Targets in Cancer Therapy.

A novel aromatic amide derivative SY-65 co-targeted tubulin and histone deacetylase 1 with potent anticancer activity in vitro and in vivo.

Tubulin degradation: Principles, agents, and applications.

Progress of tubulin polymerization activity detection methods

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Progress of tubulin polymerization activity detection methods