Repurposing of Human Tyrosine Kinase Inhibitors for Neglected Diseases

Download or read book Repurposing of Human Tyrosine Kinase Inhibitors for Neglected Diseases written by Uma Swaminathan and published by . This book was released on 2014 with total page 129 pages. Available in PDF, EPUB and Kindle. Book excerpt: *Chapter 1: Neglected tropical disease, Chagas disease and target repurposing approach* The term "Neglected Tropical Diseases" (NTDs) most commonly refers to a group of parasitic and bacterial infectious disease affecting more than one billion people globally. There are 13 core diseases in the NTD group that are widespread across the countries from sub-Saharan Africa, Asia and to Latin America. These diseases primarily occur in rural areas, urban slums or conflict zones and affect 2.7 billion people who live on less than $2 per day, causing considerable morbidity and mortality. NTDs cause severe impact on physical and cognitive development, long-term illness, impaired childhood growth and development, adverse outcomes of pregnancy and trap the poor population in a cycle of poverty and disease. Many of these diseases are neglected at the global and local level by the government and private sector owing to the poor return of drug discovery research costs. Also, the emerging resistance to the current therapies can add more burdens to the poor nations The focus of this thesis is upon finding new leads for targeting protozoan parasite "Trypanosoma cruzi", responsible for Chagas disease (CD) by using Target repurposing approach. CD affects nearly 8 million people in Latin America and increasing number of cases reported across Europe and United States. Only two FDA approved drugs are currently available for treating CD. Target repurposing approach is a viable strategy to reduce the time and expense of discovering new therapeutic molecules. In this approach a molecular target in the parasites are matched with homologous human targets that has been previously pursued for drug discovery. We can utilize this knowledge of "druggable" targets in one organism to pursue new potential drug targets in the parasites. *Chapters 2 & 3: Scaffold replacements and head group truncation using in silico models* Our lab has applied target repurposing approach to identify several novel leads against protozoan parasites responsible for causing CD, human African sleeping sickness, leishmaniasis and malaria. Kinases are an extensively pursued class of drug targets to treat several diseases like cancer, immunological and neurological disorders, inflammation and infectious diseases. Lapatinib, an FDA approved dual tyrosine kinase inhibitor (EGFR/HER2) drug for treating breast cancer was repurposed for its anti-trypanosomal properties. Extensive SAR studies of lapatinib analogs led to sub-micromolar potent compound 1.25 (Figure 1.9) against the parasite "T. brucei". Hypothesizing that other parasites express similar kinase pathways, these libraries of compound were screened against other related parasites, which resulted in several lead compounds of micromolar potency. Encouraged by these results, we advanced our work to a scaffold replacement strategy. This resulted in the discovery of a potent lead 2.25b (Figure 2.6) with 0.09 μM activity against "T. cruzi". Despite having a good efficacy, the lead compound failed in the in vivo animal studies due to poor physicochemical properties. In an attempt to improve the physicochemical properties, we adopted a head group replacement strategy for the lead compound based on molecular modelling and virtual screening tools. The concept of ligand efficiency (LE) and lipophilic ligand efficiency (LLE/LiPE) were introduced with an aim to identify new leads. Finally, an attempt was made to establish a possible structure activity relationship (SAR) from the screening data of all the library series. *Chapter 4: Future directions* Final chapter summarizes the results of this thesis and provides the futuristic plan for the advancement of the current work to identify potent leads for Chagas disease.