Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin

Abstract

Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

“…In particular, compound 9, characterized by 2-aminopyrimidyl- and trichloroethyl- moieties, similarly to those in Apcin, showed a preferential efficacy in hematology compared with solid tumor models, and significantly reduced the growth of AML and ALL cells. Moreover, Huang and colleagues synthesized a series of 2,2,2-trichloro-1-aryl carbamate derivatives starting from the modification of Apcin structure [ 159 ]. They identified two compounds, namely 7d and 9f showing a higher efficacy compared with Apcin in terms of mitotic arrest and apoptosis induction, which occurred through stabilization of CCNB1 and activation of caspase-3 and PARP, respectively.…”

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

“…On the basis of the modification of cell division cycle 20 homologue (Cdc20) specific inhibitor apcin, Huang et al 161 discovered a dual tubulin−Cdc20 inhibitor 71 (Figure 17A). It showed a similar Cdc20 binding affinity compared to apcin (71, K D = 119 μM; apcin, K D = 123 μM).…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…Compound 25 displayed concentration-dependent inhibition of porcine tubulin assembly and also caused concentration-dependent accumulation of HCT116 and SW620 cells in the G 2 /M cell cycle phase at 25-100 nM concentrations. In addition, this compound displayed activity against other colorectal cancer cell lines (SW480, IC 50 26), a substituted 2-aminopyrimidine compound [45]. Compound 26 is a specific inhibitor of Cdc20, a protein which activates the key E3 ubiquitin ligase APC/C that controls cell cycle progression; Cdc20 is overexpressed in several cancers (see Reference [46] for a review of Cdc20 as an anticancer target).…”

“…Huang et al designed new purine and pyrimidine molecules based on the structural modification of apcin ( 26 ), a substituted 2-aminopyrimidine compound [ 45 ]. Compound 26 is a specific inhibitor of Cdc20, a protein which activates the key E3 ubiquitin ligase APC/C that controls cell cycle progression; Cdc20 is overexpressed in several cancers (see Reference [ 46 ] for a review of Cdc20 as an anticancer target).…”