Novel ATP-Competitive Kinesin Spindle Protein Inhibitors

Abstract

Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.

Kinesin motor proteins as targets for cancer therapy

“…Mutations in this binding pocket have been shown to result in resistance to ispinesib, providing a mechanism for drug resistance [120][121]. Recent identification of several series of ATP competitive inhibitors that appear to bind in a region distinct from that of the L5 loop may provide an avenue to overcome this obstacle [122][123][124]. Examples are shown in Fig.…”

“…10. Some compounds from these series have been shown to overcome resistance and induce significant anti-tumour effects in mutant-KSP models, however reduced efficacy was noted with wildtype tumours [123]. Development of selective ATP-competitive inhibitors that can be used clinically, in combination with an allosteric inhibitor, could prove beneficial in overcoming resistance that might arise from target mutation.…”

Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

“…Others, like the thiazolecontaining inhibitors, are competitive with ATP and uncompetitive with microtubules. Interestingly, biaryl compounds, such as GSK-1 and GSK-2, do not bind in the nucleotidebinding pocket, but they antagonize ATP interactions through an allosteric mechanism, proven by site-directed mutagenesis and photo-affinity labeling (28,29). The natural product, adociasulfate-2, also acts in a unique manner, as it is not competitive with ATP binding, but interferes with the microtubule-binding site (30).…”

Potential new chemotherapy strategy for human ovarian carcinoma with a novel KSP inhibitor

“…Subsequent inhibitors of the ATPase activity of KSP that have been reported include the dihydropyrimidine-2-thione derivative dimethylenastron [7,8], the quinazolinone derivatives ispinesib [9] and SB-743921 [10], the dihydropyrrole derivative MK-0731 [11], the tetrahydroquinoline derivative EMD-534085 [12], the cysteine derivative S-trityl-L-cysteine [13], and a biphenyl derivative [14]. Some of these KSP inhibitors have undergone clinical trials [10,15e21].…”