Kinase Scaffold Repurposing for Neglected Disease Drug Discovery: Discovery of an Efficacious, Lapatanib-Derived Lead Compound for Trypanosomiasis

Abstract

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. Since drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogs of 1, which provided an excellent starting point for optimization of the chemotype. We report our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU621, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new tool for studying regulation of the trypanosome cell cycle.

New Chemical Scaffolds for Human African Trypanosomiasis Lead Discovery from a Screen of Tyrosine Kinase Inhibitor Drugs

“…Specifically, the 4-anilinoquinazoline and pyrrolopyrimidine chemical entities might be the focus of a medicinal chemistry scaffold repurposing effort. The goals advanced here are achievable, as demonstrated recently with derivatives of lapatinib and danusertib (28,48). Finally, we recognize that a significant number of HAT patients present with late-stage disease, when the trypanosome has crossed the blood-brain barrier (reviewed in reference 9).…”

“…In this proof-of-concept study CI-1033 and AEE788 improved the mean survival of infected mice without curing the disease. These observations bode well for attempts to optimize 4-anilinoquinazoline or pyrrolopyrimidine scaffolds as leads for antitrypanosomal drug discovery (28).…”

“…Either way, these observations highlight the notion that new synthetic 4-anilinoquinazoline derivatives might be produced against T. brucei, using lessons learned from comparing the structures of lapatinib and CI-1033. In support of this principle, the Pollastri group has synthesized nine new lapatinib derivatives that are 5 to 30 times more potent than lapatinib in whole-cell screening assays (28). Thus, 4-anilinoquinazoline is a good scaffold for antitrypanosomal lead optimization.…”

“…Only a few drugs, none of which are administered orally, are used for treating human African trypanosomiasis (HAT) (reviewed in references 9 and 46). Due to the high cost of discovering new drugs (47) and the reality that the field is underfunded because pharmaceutical companies do not consider drug discovery for diseases of poverty profitable, a piggyback drug discovery strategy of using existing drug scaffolds as the template for synthesizing new leads against trypanosomes has been advocated (10,11,22,28,48). One path to reducing the total cost of identifying new chemical entities for antitrypanosomal drug discovery is to perform an initial focused screen, where the search for novel antit- rypanosomal scaffolds is guided by the basic biology of the trypanosome (see reference 49 for a perspective).…”

Novel Effects of Lapatinib Revealed in the African Trypanosome by Using Hypothesis-Generating Proteomics and Chemical Biology Strategies

“…Further, we note that the 4-anilinoquinazoline scaffold of lapatinib is present in other marketed drugs (e.g., gefitinib, erlotinib). Considering these facts, we have initiated projects to improve potency of the 4-anilinoquinazole scaffold and its derivatives against trypanosomes with great success (6)(7)(8). The next stage of the drug development process, which is ongoing, involves improvement of pharmacokinetic properties as well as adsorption, distribution, metabolism, and excretion (ADME) in vertebrate animals, for example, increasing central nervous system (CNS) penetrance.…”