Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

Abstract

BackgroundSchistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets.Methodology/Principal FindingsWe show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti-schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1–2 μM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays.Conclusions/SignificanceThe reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti-schistosomals.

Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target

“…g ., rounding, degeneration, overactivity and slowed motility) as described [99–101]. For adult parasites, in addition to observation-based annotations, we employed Wormassay [102] to measure worm motility.…”

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening

“…This is an important feature for a new antischistosomal drug because modern lead discovery pipelines prioritize compounds that possess bioactivity across the entire developmental cycle of the parasite in the mammalian host. 73,74 …”

Quantifying the mechanics of locomotion of the schistosome pathogen with respect to changes in its physical environment

“…This new capacity could complement recent advances in the multi-parametric characterization of schistosome phenotypic space in response to drug insult (8,(61)(62)(63). Future efforts shall focus on establishing proof-of-concept of these parameters for drug discovery with particular attention to their 20 sensitivity and specificity, and address the scalability of the proposed methodologies to higher throughput.…”

“…Schistosomes possess a muscular system made up of circular, oblique and longitudinal muscles intricately interlaced with a nervous system that utilizes both classical and peptidergic signaling (4)(5)(6). This neuromuscular complexity results in a remarkable plasticity in parasite shape and movement (7,8). Further, the parasite possesses anteriorly-positioned oral and ventral suckers which, presumably, help maintain position in the venous system and aid locomotion.…”