Reoptimization of human kinase inhibitors for the treatment of neglected tropical diseases

Abstract

Neglected tropical diseases (NTDs) represent a major burden to the tropical and sub-tropical countries. Despite the large number of people impacted by these diseases, the investment from the pharmaceutical industry has not been proportionate to the problem at hand. This is due to a myriad of factors, but perhaps the largest factor is the impoverished nature of those impacted by NTDs; because the patient population does not have the finances to support investment from industry in multi-year, highly expensive and risky drug discovery campaigns. This has meant that the driving force behind NTD drug discovery has been academia, non-profit organizations, and industrial-academic collaborations. These organizations do not have the same man-power or resources that a traditional industrial drug discovery campaign would have available. To help bridge this gap in resources, we employed different repurposing techniques to help accelerate the drug discovery timeline. The work discussed in this dissertation is split between two repurposing techniques: lead and target class repurposing. Both of these strategies used chemical matter that had previously been studied against human kinase targets, granting us more information than would typically be available at the outset of a drug discovery campaign, helping to shorten our timeline and focus our efforts. Chapter 2 of this dissertation discusses the work performed in a lead repurposing campaign for the treatment of human African trypanosomiasis (HAT), which is caused by the parasite Trypanosoma brucei. From a high-throughput screen (HTS) of 42,444 known kinase inhibitors, the pyrazolo[1,5-b]pyridazines were identified, as fast-acting, cidal, and central nervous system (CNS) active compounds. Optimization efforts were split into improving the absorption, distribution, metabolism, and excretion (ADME) properties, and improving the selectivity over three known human kinase targets: GSK-3β, CDK-2, and CDK-4. Optimization for selectivity resulted in NEU-4990, which was > 10-fold selective over all three human kinases. Efforts to improve the ADME properties resulted in NEU-4932, which showed desirable pharmacokinetics (PK), as well as CNS activity. Efficacy studies of NEU-4932 showed that while toxic, the compound did significantly reduce parasitemia in four out of six mice. Chapter 3 of this dissertation focuses on a target class repurposing campaign that was undertaken to repurpose a human cancer drug, lapatinib, for the treatment of Chagas disease which is caused by the parasite Trypanosoma cruzi. Three areas of the molecule: the core, tail and head, were explored, and a new cyanoquinoline core was identified that was both active against T. cruzi and selective over human HepG2 cells. Exploration of aliphatic head groups resulted in NEU-5820 which showed vastly improved solubility over the rest of the series and good activity against T. cruzi. NEU-5820 was progressed to a PK study where it was found to be highly toxic, and not orally bioavailable. Nonetheless, compounds in the series were found that show promise against both T. b. brucei¸ as well as L. donovani.