CPUYJ039, a newly synthesized benzimidazole-based compound, is proved to be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity

Abstract

These results suggest that CPUYJ039 may be a novel inducer of apoptosis in HCT116 cells with potent KSP inhibitory activity.

Multicomponent Assembly of the Kinesin Spindle Protein Inhibitor CPUYJ039 and Analogues as Antimitotic Agents

“…The values are consistent with previous studies.25 Table2. IC 50 Values (μM) of 8d, 8e, and 8g and References CPUYJ039 and STLC in Mitotic Arrest and KSP ATPase a The values (μM) are the means of three independent experiments with standard deviations shown in parentheses.b Values previously reported by Jiang and co-workers 11. Their results indicate CPUYJ039 with a mitotic arrest IC 50 value of >16 μM in the treatment of HCT116 cells with CPUYJ039 for 24 h. Their enzyme assay conditions were different from ours in the concentrations of KSP protein, microtubules, and ATP.…”

“…11 Despite the high in vitro activity of this molecule (IC 50 = 40 nM, KSP-ATPase test), 11 its cytotoxicity in HTC116 cells is low (EC 50 = 2.30 μM). 11 You and co-workers proposed permeability problems as the cause of this low activity, 11 but this is unclear considering the good cellular activity shown by another series of similar benzimidazoles that target KSP. 13 The only experimental procedures described for the synthesis of CPUYJ039 and the related amino-free benzimidazoles are linear 7-or 8-step procedures, respectively, described by Boyce (Chiron Patent) 14 that uses 2nitroanilines as starting materials (Scheme 1).…”

“…These compounds are frequently used as model ligands for the evaluation of anti-KSP activity . However, the most advanced clinical trials (phase I and phase II clinical trials, either as monotherapies or in combination with other drugs) have been carried out using the prototypes that contain a central planar heterocycle attached to an exocyclic 2-(1-( N -(3-aminopropyl)­benzamido)­alkylic framework (Figure B), such as Ispinesib, SB-743921, pyrrolotrizine-1 (BMS-24), AZD4877, CK0106023, and CPUYJ039, all of which target the L5/α2/α3 pocket of KSP . The presence of a basic amino or dimethylamino group at the end of the aminopropyl-type chain in these molecules often increases the specificity in targeting KSP.…”

“…For instance, the linear syntheses of Ispinesib, SB-743921, and Pyrrolotrizine require eight steps, and the preparation of AZDD4877 involves 13 transformations . CPUYJ039 is a potent KSP inhibitor, and it contains benzimidazole as a central core . Despite the high in vitro activity of this molecule (IC 50 = 40 nM, KSP-ATPase test), its cytotoxicity in HTC116 cells is low (EC 50 = 2.30 μM) .…”

Pharmacokinetic Evaluation of a Novel Benzopyridooxathiazepine Derivative as a Potential Anticancer Agent

“…There are two major groups of these antimitotic agents: microtubule stabilizers such as paclitaxel and microtubule destabilizers such as vinca alkaloids, chalcones and chalcone derivatives, colchicine, combretastatin A-4, and sulfonamide E7010 [1,2,3,4,5,6]. However, these agents which target microtubules have high toxicity, and their potency is limited by the development of multidrug resistance [7,8]. Therefore, there has been great interest in developing novel microtubule inhibitors that overcome various modes of resistance and exhibit improved pharmacological profiles.…”