Anthelmintics Derived from the Kinase Inhibitor SGI-1776 for the Treatment of Gastrointestinal Worm Infections

Human gastrointestinal nematodes (GINs) infect at least one billion people, mostly children, with five billion people at risk of infection. Reduced and low efficacy of currently used anthelmintics, e.g., benzimidazoles against Trichuris trichiura whipworms, urges new anthelmintics to control these parasites. We previously discovered two human pan-PIM kinase inhibitors, CX-6258 and SGI-1776, with potent antihelmintic activity against GINs. Here, structure–activity relationship (SAR) studies were conducted to identify SGI-1776 analogs with improved cross-clade adulticidal activity (Ancylostoma ceylanicum hookworms and Trichuris muris whipworms). We further identified a new chemical series from 15 (imidazo[1,2-b]pyridazine-3-carboxamide) and novel derivatives from it. Differential cuticle permeability, quantified by the amount of bioaccumulated drugs, explained some unexpected observations regarding activity and correlated with their physicochemical properties. The compounds’ physical properties were significantly predictive of their activity. 15 and 51 were the most potent against whipworm and showed decreased and no activity against human PIM kinases, suggesting increased selectivity against the GIN counterparts. The unexpected SAR of compound 15 can be explained by computational modeling. We demonstrate the efficacy of optimized compound 50 as a new oral anthelmintic, which demonstrated better gut restriction properties and significantly reduced the fecundity of T. muris whipworm adults in infected mice. We also report our findings on physicochemical properties and gut restriction ADME parameters that are essential for further lead optimization.

人体胃肠道线虫（gastrointestinal nematodes, GINs）至少感染全球10亿人，其中多为儿童，另有50亿人存在感染风险。当前使用的驱虫药（如针对毛首鞭形线虫（Trichuris trichiura，又称鞭虫）的苯并咪唑类药物）疗效下降且偏低，亟需开发新型驱虫药物以防控这类寄生虫。本课题组此前已发现两种人体泛PIM激酶抑制剂CX-6258与SGI-1776，二者对胃肠道线虫展现出强效的抗蠕虫活性。本研究开展了构效关系（structure-activity relationship, SAR）研究，旨在筛选出SGI-1776的类似物，使其具备更优异的跨分支成虫杀灭活性，针对的虫株包括锡兰钩虫（Ancylostoma ceylanicum）与鼠鞭虫（Trichuris muris）。本研究进一步从化合物15（咪唑并[1,2-b]哒嗪-3-甲酰胺）中发掘出一类全新的化学骨架，并获得了该骨架下的多款新型衍生物。通过药物生物蓄积量量化得到的体壁通透性差异，可解释部分与活性相关的意外实验结果，且该通透性与化合物的理化性质显著相关。化合物的物理性质可显著预测其抗蠕虫活性。化合物15与51对鞭虫的活性最为强劲，且对人体PIM激酶的活性分别出现下降乃至完全丧失，这提示二者针对胃肠道线虫对应靶点的选择性显著提升。化合物15的意外构效关系可通过计算建模手段予以解释。本研究证实了优化后的化合物50作为新型口服驱虫药的药效：该化合物展现出更优异的肠道滞留特性，可显著降低感染小鼠体内鼠鞭虫成虫的繁殖能力。本研究同时报道了与理化性质及肠道滞留ADME（吸收-分布-代谢-排泄）参数相关的实验结果，这些参数对后续先导化合物优化至关重要。