Microtubule (MT) targeting agents (MTAs), that disrupt MT dynamics through stabilization or depolymerization, are well-established as anti-tumor therapeutics. However, better MTAs with enhanced properties, such as fewer side effects, more discrete targeting, and less susceptibility to drug resistance, are in high demand. Recent work by Shan et al. identified a novel MTA that may function as a next-generation MT-targeting chemotherapeutic. Initial virtual screening studies of the Specs library containing over 200,000 compounds were performed in order to identify molecules that target the taxane (stabilizing drug) or colchicine (depolymerizing drug) MT-binding sites. Of the 93 potential candidates identified, two (compounds 82 and 89) produced robust antiproliferative MTS measurements in tumor cell lines. Further characterization showed that compound 89 was the most promising molecule and successfully inhibited the proliferation, migration, and invasion of tumor cells. Biochemical studies showed that compound 89 bound tubulin and prevented in vitro polymerization, similar to colchicine. Interestingly, some of the effects of compound 89 are dependent on the PK3K/Akt pathway, as administration of recilisib, a P13K activator, could reverse some of the effects on MTs. Compound 89 also showed reduced tumor growth and metastasis in mouse models, and also displayed anti-tumor activity in human tumor organoids. Promisingly, compound 89 did not appear to show systemic toxicity in mice. Collectively, the group identified a novel tubulin inhibitor that displays promising anti-tumor capability and may function as a template for the development of a next-generation MTA. Cytoskeleton Inc.’s Tubulin polymerization assay (Cat. # BK006P) was a critical tool used for characterizing its direct effects on tubulin polymerization.
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Tubulin polymerization assay using >99% pure tubulin, OD based - Porcine (Cat # BK006P)
