{"id":1282,"date":"2019-08-10T18:54:51","date_gmt":"2019-08-10T10:54:51","guid":{"rendered":"http:\/\/www.bioactivescreeninglibrary.com\/?p=1282"},"modified":"2022-01-07T10:54:17","modified_gmt":"2022-01-07T02:54:17","slug":"antitubulin-activity-responsible-selective-cytotoxicity-tumorigenic-cell-lines","status":"publish","type":"post","link":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/2019\/08\/10\/antitubulin-activity-responsible-selective-cytotoxicity-tumorigenic-cell-lines\/","title":{"rendered":"Antitubulin activity is likely to be responsible for selective cytotoxicity against tumorigenic cell lines"},"content":{"rendered":"

Subsequent analysis of the scientific literature revealed that many of our compounds do indeed inhibit polymerization of Carfilzomib<\/a> tubulin in vitro. Compound 384634 has been synthesized and has shown to demonstrate antitublin activity in a tubulin polymerization assay. Likewise, isosteres of compound 385177, 5468780 and 5468781 potently inhibit tubulin polymerization. It is highly plausible that compound 379512 is an antitubulin agent as well, because a number of compounds containing the 2-phenylquinolone ring structure have been synthesized and exhibit tubulin polymerization. Compound 5388755 is almost structurally identical to Combretastatin A-4, which is a very potent antitubulin agent. COMPARE analysis was performed to further characterize the mechanism of action of the compounds. In COMPARE, a correlation coefficient of 0.6 is generally taken to indicate evidence for similar mechanisms of action between the tested and reference compounds. The higher the correlation coefficient, the more likely it is that the compounds share the same intracellular target. The correlation coefficient of the COMPARE computations for the eight most potent compounds and the antimitotic standard anticancer PD 0332991<\/a> agents reveals several compounds showing high correlations with microtubule inhibitors colchicine, maytansine, vinblastine and vincristine. None of these compounds show similarity to any of the agents from other mechanistic classes such as topoisomerase inhibitors, alkylating agents and DNA\/RNA antimetabolites. None of the compounds exhibit strong correlation with taxol, which is an antimitotic agent that acts by stabilizing microtubules. In order to identify the role of antitubulin activity in generating selective cytotoxicity, we identified twelve additional DTP compounds that are structurally related to some of the nine compounds we identified in our correlation analysis but that lack antitubulin activity. If antitubulin activity confers selective cytotoxicity, these compounds with no antitubulin activity should demonstrate no selective cytotoxicity. The scatterplot comparing the association between cytotoxicity and take-rate for these twelve compounds indicates that none of these compounds show selective cytotoxicity, and they are largely inactive in the cell growth inhibition assay. By data mining the DTP archive, we are able to identify compounds that are preferentially toxic against the most tumorigenic of the NCI60 cell lines, based on the take rate of the cell lines in a mouse xenograft model. We also established that the activity of these compounds was not correlated to the expression of cell surface stem cell markers reported in the literature. Nevertheless, tumorigenic potential is the most important functional relationship between the most aggressive tumor cells and in vitro model for drug screening. Therefore, the anticancer agents identified based on their activity against the most tumorigenic cell lines may be considered as candidate anticancer agents that are specifically directed against subpopulations of cancer cells that drive the growth of tumors. One of these agents has been found to inhibit microtubule polymerization. Likewise, isosteres of three of our agents have also been shown to inhibit microtubule polymerization, suggesting a single mechanism of action. Interestingly, Compound 5388755 is structurally related to the potent antitubulin agent Combretastatin A-4. It is also possible that compound 379512 acts by inhibiting tubulin polymerization because several different agents containing the quinolone ring structure have demonstrated antitubulin activity. COMPARE analysis corroborates the similarities between the anticancer agents identified here and various different microtubule inhibitors. With the exception of compound 319428, all of our compounds show strong similarity with colchicine, maytansine, vinblastine and vincristine. None of our compounds show significant relationship to taxol, which acts by stabilizing microtubules.<\/p>\n","protected":false},"excerpt":{"rendered":"

Subsequent analysis of the scientific literature revealed that many of our compounds do indeed inhibit polymerization of Carfilzomib tubulin in vitro. Compound 384634 has been synthesized and has shown to demonstrate antitublin activity in a tubulin polymerization assay. Likewise, isosteres of compound 385177, 5468780 and 5468781 potently inhibit tubulin polymerization. It is highly plausible that … Continue reading “Antitubulin activity is likely to be responsible for selective cytotoxicity against tumorigenic cell lines”<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1],"tags":[],"_links":{"self":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1282"}],"collection":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/comments?post=1282"}],"version-history":[{"count":1,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1282\/revisions"}],"predecessor-version":[{"id":1283,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1282\/revisions\/1283"}],"wp:attachment":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/media?parent=1282"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/categories?post=1282"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/tags?post=1282"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}