Repurposing human kinase inhibitor chemotypes for Neglected Tropical Diseases

摘要/文摘

SUMMARY/ABSTRACT Human African trypanosomiasis (HAT) and Chagas disease (CD) are neglected tropical diseases (NTDs). Current drugs show increasing numbers of treatment failure, low efficacy, difficult treatment regimens or severe side effects. In a unique industrial-academic collaboration, the PIs, in collaboration with GSK, ran a high-throughput screen (HTS) of ~46,000 kinase-targeted inhibitors against Trypanosoma brucei, the causative agent of HAT. This resulted in the discovery of 797 potent (T brucei EC50<1 μM; pEC50 6) and selective hits (>100-fold over HepG2 cells) that were sorted into 59 structural clusters, plus 53 singletons. 14 chemotypes including 13 clusters and 1 singleton have been explored for their structure-activity and structure-property relationships. A “parasite-hopping” approach has identified six of these with interesting activity against T cruzi (CD). This competitive renewal outlines a hit-to-lead medicinal chemistry program that will continue to optimize high-priority hit clusters from the original HTS. These have been identified through re-analysis of the original HTS data to place an emphasis on compounds that are cidal and predicted to cross the blood-brain barrier (BBB) which is essential to treat stage 2 of HAT. Additionally, we will employ computer-aided drug discovery to further explore those chemotypes for which we have identified a putative target. We will also perform hit-to-lead medicinal chemistry optimization on the six chemotypes that have been identified as of interest for T cruzi. We will also look for synergistic effects between clusters that have complementary activity profiles (e.g. slow acting, cidal in nature, and fast acting, static in nature) and in combination with standard trypanocidal drugs. Optimization will result in the delivery of high-quality lead compounds from each of these chemical classes, and the lead compounds will meet stringent profiles of cellular potency and selectivity, BBB permeability, physicochemical and metabolic properties, and pharmacokinetic properties in mice depending on the disease targeted. Furthermore, these lead series will display in vivo efficacy in the murine models of disease. The optimization program will be performed under the continuing collaboration between NEU and CSIC, with critical contributions of expertise in drug metabolism and physicochemical properties experiments from AstraZeneca and UCSD. We have developed and implemented a testing funnel that ensures that the optimization process will address the most critical lead criteria. Finally, we will perform the target identification and mode of action studies by different approaches including chemical proteomics, induction of resistance and whole genome sequencing and metabolic fingerprinting. This project will deliver (a) multiple lead compounds for HAT and CD that meet well-defined Lead Criteria; (b) broader profiling of lead compounds against more stringent Candidate Criteria; (c) identification of target for lead series or compound. In this way, we intend to help fill the pre-clinical candidate pipeline for HAT and CD.