Discovery of Human PIM Kinase Inhibitors as a Class of Anthelmintic Drugs to Treat Intestinal Nematode Infections

Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human and animal health, with limited treatment options and emerging drug resistance. Trichuris trichiura (whipworm) stands out as a neglected disease, necessitating new drugs to address this unmet medical need. We discovered that several different chemical series of related human Provirus Integration sites for Moloney murine leukemia virus (PIM) family kinase inhibitors possess potent anthelmintic activity by using whole-worm motility assays. Systematic structure–activity relationship (SAR) studies based on the pan-PIM kinase inhibitor CX-6258 were conducted to identify compounds displaying improved in vitro motility inhibition of both adult hookworm (Ancylostoma ceylanicum) and adult whipworm (Trichuris muris) nematodes. A broad kinase selectivity screen of >450 human kinases confirms PIM1 kinase and others as potential targets for CX-6258 and analogues thereof. In addition, we demonstrated that CX-6258 significantly reduced worm burden and egg counts in the T. muris infection model of mice, establishing it as a new oral small molecule anthelmintic therapeutic.土源性蠕虫（Soil-transmitted helminth, STH）感染累及全球四分之一的人口，对人类及动物健康造成重大威胁，当前治疗手段有限且伴随日益凸显的耐药性问题。毛首鞭形线虫（Trichuris trichiura，俗称鞭虫）属于被忽视的热带病范畴，亟需新型药物来填补这一未被满足的医疗需求。本研究借助全蠕虫运动试验，发现多款隶属于不同化学系列的人类莫洛尼鼠白血病病毒（Moloney murine leukemia virus）前病毒整合位点（PIM）家族激酶抑制剂，均具备强效抗蠕虫活性。基于广谱PIM激酶抑制剂CX-6258开展了系统性构效关系（Structure-Activity Relationship, SAR）研究，旨在筛选出对成年锡兰钩口线虫（Ancylostoma ceylanicum）与成年鼠鞭虫（Trichuris muris）均具有更优异体外运动抑制活性的化合物。针对超过450种人类激酶的广谱激酶选择性筛选结果证实，PIM1激酶及其他激酶可作为CX-6258及其类似物的潜在作用靶点。此外，本研究在鼠鞭虫感染小鼠模型中验证了CX-6258可显著降低蠕虫荷重与虫卵计数，从而确立其作为新型口服小分子抗蠕虫治疗药物的应用潜力。