MT7, a novel compound from a combinatorial library, arrests mitosis via inhibiting the polymerization of microtubules

Abstract

Targeting cellular mitosis is an attractive antitumor strategy. Here, we reported MT7, a novel compound from the 6H-Pyrido[2',1':2,3]imidazo [4,5-c]isoquinolin- 5(6H)-one library generated by using the multi-component reaction strategy, as a new mitotic inhibitor. MT7 elicited apparent inhibition of cell proliferation by arresting mitosis specifically and reversibly in various tumor cell lines originating from different human tissues. Detailed mechanistic studies revealed that MT7 induced typical gene expression profiles related to mitotic arrest shown by cDNA microarray assays. Connectivity Map was used to analyze the microarray data and suggested that MT7 was possibly a tubulin inhibitor due to its similar gene expression profiles to those of the known tubulin inhibitors demecolcine, celastrol and paclitaxel. Further analyses demonstrated that MT7 inhibited the polymerization of cellular microtubules although it was not detectable to bind to purified tubulin. The inhibition of cellular tubulin polymerization by MT7 subsequently resulted in the disruption of mitotic spindle formation, activated the spindle assembly checkpoint and consequently arrested the cells at mitosis. The persistent mitotic arrest by the treatment with MT7 led the tested tumor cells to apoptosis. Our data indicate that MT7 could act as a promising lead for further optimization, in hopes of developing new anticancer therapeutics and being used to probe the biology of mitosis, specifically, the mode of interference with microtubules.

Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

“…We reported that specific compounds can directly kill MDR tumor cells without affecting the function of P-gp, such as the natural products salvicine (3,4), pseudolaric acid B (5, 6), methyl spongoate (7), tanshinone I (2,8), and synthetic small molecules YCH337 (9) and MT series (10)(11)(12). Among them, the MDRovercoming activities of natural products were associated with the regulation of certain transcription factors.…”

MCL-1 Degradation Mediated by JNK Activation via MEKK1/TAK1-MKK4 Contributes to Anticancer Activity of New Tubulin Inhibitor MT189

“…We previously reported MT7 and MT119 derived from a combinatorial library of 6H-Pyrido[2 0 ,1 0 :2,3]imidazo [4,5-c]isoquinolin-5(6H)-ones as colchicine site-targeted tubulin inhibitors (2-4). They are new chemical entities with a distinct mode of tubulin polymerization inhibition from colchicines, but disappointingly, both do not show in vivo anticancer activity (3,4). MT189 is a newest analog of this series, obtained by taking a deconstruction approach to break the tetracyclic ring of MT119.…”

“…Both cause microtubulin depolymerization, persistent M phase arrest, and apoptosis. MT119 was confirmed to bind to the colchicine site on tubulin (3)(4)(5). Although both produce potent in vitro antiproliferative effects and overcome tumor multidrug resistance (MDR), they did not show obvious in vivo anticancer activity.…”

“…Both M arrest and apoptosis contribute to their anticancer effects (3,4,6). Besides, other mechanisms of action and/ or signaling pathways might be involved.…”

Identification of DW532 as a novel anti-tumor agent targeting both kinases and tubulin

“…The percent of mitotic cells was quantified by flow cytometry as previously described [14] . Briefly, MDA-MB-468 cells were treated with or without DW532 or siRNA for the indicated time.…”