Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies

Bringing to a halt the cell cycle in mitosis and interfering with its normal progression is one of the most successful anti-cancer strategies used nowadays. Classically, several kinds of anti-cancer drugs like taxanes and vinca alkaloids directly inhibit microtubules during cell division. These drugs exhibit serious side effects, most importantly, severe peripheral neuropathies. Alternatively, KSP inhibitors are grasping a lot of research attention as less toxic mitotic inhibitors. In this review, we track the medicinal chemistry developmental stages of KSP inhibitors. Moreover, we address the challenges that are faced during the development of KSP inhibitor therapy for cancer and future insights for the latest advances in research that are directed to find active KSP inhibitor drugs. Plain language summary: Scientists have recognized the importance of selective KSP inhibitors in the early 2000s and so various KSP protein inhibitors have been investigated. Only ten of these have been clinically evaluated for cancer treatment. Ispinesib (SB-715992) and filanesib (Arry-520) were the most promising small molecules in clinical trials against the KSP protein. Many challenges are faced during the development of an active anti-KSP drug; most importantly are the unsatisfactory clinical trial results. Designing dual inhibitors, antibody-drug conjugates, combination therapy and gene therapy approach are among the main strategies that are being investigated nowadays to find new effective KSP inhibitors. The scientific research efforts are still devoted to find an effective and tolerable KSP inhibitor drug that can gain US FDA approval. [GRAPHICS] .

Automated summary

Halting the cell cycle in mitosis and interfering with its normal progression is an effective anti-cancer strategy. Traditional anti-cancer drugs directly inhibit microtubules during cell division, but they have serious side effects. On the other hand, KSP inhibitors are receiving attention as less toxic mitotic inhibitors. This review tracks the medicinal chemistry developmental stages of KSP inhibitors and discusses the challenges and future insights in developing active KSP inhibitor drugs for cancer treatment.