Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers

Abstract
Screening custom-designed inhibitor libraries can uncover potential drugs for treating pancreatic cancer. Through this approach, we identified ispinesib as a promising candidate and sought to evaluate its clinical effectiveness, along with the biological significance of its target, Eg5, in pancreatic cancer. We screened 100 compounds from our library using cell cytotoxicity assays to identify potential drug candidates, and ispinesib was found to exhibit strong antitumor activity in pancreatic cancer. To assess the clinical relevance of Eg5 expression, we conducted immunohistochemical staining on tumor samples from 165 pancreatic cancer patients and analyzed Eg5-positive patient-derived xenograft (PDX) mouse models. We found that patients with Eg5-positive tumors had significantly worse clinical outcomes compared to those without Eg5 expression (overall survival; P < .01, recurrence-free survival; P < .01). Additionally, treatment with ispinesib or silencing Eg5 using specific siRNA markedly inhibited cell proliferation and triggered apoptosis in pancreatic cancer cell lines. On a molecular level, ispinesib caused incomplete mitosis and nuclear disruption, leading to multinucleated cells with monoastral spindles. In PDX mouse models, ispinesib significantly reduced tumor growth compared to the vehicle control (mean tumor volume: 652.2 mm³ vs. 18.1 mm³, P < .01 by ANOVA; tumor weight: 545 mg vs. 28 mg, P < .01 by ANOVA). Our findings suggest that ispinesib, discovered through inhibitor library screening, holds promise as a novel therapeutic agent for pancreatic cancer. Furthermore, Eg5 expression is linked to poorer postoperative prognosis and plays a crucial role in the clinical effectiveness of ispinesib in pancreatic SB-715992 cancer treatment.