Role of KSP Inhibitors as Anti-Cancer Therapeutics: An Update

Abstract

Regardless of the growing discovery of anticancer treatments, targeting cancer-specific pathways, cytotoxic therapy still maintained its abundant clinical significance based on the fact that tumours harbour a greater population of actively dividing cells than normal tissues. Conventional anti-mitotic agents or microtubule poisons acting on the major mitotic spindle protein tubulin have been effectively used in clinical settings for cancer chemotherapy over the last three decades. However, use of these drugs is associated with limited clinical utility due to serious side effects such as debilitating and dose-limiting peripheral neuropathy, myelosuppression, drug resistance and allergic reactions. Therefore, research initiatives have been undertaken to develop novel microtubule motor proteins inhibitors that can potentially circumvent the limitations associated with conventional microtubule poisons. Kinesin spindle proteins (KSP) belonging to the kinesin-5 family play a crucial role during mitosis and unregulated cell proliferation. Several evidences from preclinical studies and different phases of clinical trials have presented kinesin spindle protein as a promising target for cancer therapeutics. kinesin spindle protein inhibitors causing mitosis disruption without interfering with microtubule dynamics in non-dividing cells offer a potential therapeutic alternative for the management of several major cancer types and are devoid of side effects associated with classical anti-mitotic drugs. This review summarizes recent data highlighting progress in the discovery of targeted KSP inhibitors and presents the development of scaffolds, structure–activity relationships, and outcomes of biological, and enzyme inhibition studies. We reviewed the recent literature reports published over last decade, using various electronic database searches such as PubMed, Embase, Medline, Web of Science, and Google Scholar. Clinical trial data till 2021 was retrieved from ClinicalTrial.gov. Major chemical classes developed as selective KSP inhibitors include dihydropyrimidines, β-carbolines, carbazoles, benzimidazoles, fused aryl derivatives, pyrimidines, fused pyrimidines, quinazolines, quinolones, thiadiazolines, spiropyran and azobenzenes. Drugs such as filanesib, litronesib, ispinesib have entered clinical trials, the most advanced phase explored being Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.

The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside

“…Although the phased outcomes are not yet satisfactory, some hopeful advantages can also be observed like decreased neurotoxicity compared with taxanes, as well as the potential of Arry-520 (filanesib in clinical) in the treatment of relapsed or intractable multiple myeloma. The relevant clinical trial results are well reviewed in [ 160 , 168 ], due to space constraints, we will not go into details here. In regard to hepatobiliary carcinomas, observations from the phase II trial of SB-715992 (a KSP-targeted inhibitor) failed to show the superiority of monotherapy for patients with metastatic HCC, although the treatment was well tolerated [ 169 ].…”

Design, Synthesis, Antitumour Evaluation, and In Silico Studies of Pyrazolo-[1,5-c]quinazolinone Derivatives Targeting Potential Cyclin-Dependent Kinases

“…Research has shown that some compounds with a quinazoline core can inhibit cell proliferation, induce apoptosis, and impede angiogenesis, and they have the ability to modulate signal transduction pathways and target specific proteins [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. As shown in Figure 1 A, ispinesib [ 10 , 11 , 12 ] is a potent inhibitor of kinesin spindle protein (KSP), which plays a role as a key regulator of cell mitosis. By inhibiting KSP, ispinesib disrupts cell division and hinders the growth and spread of cancer cells.…”