This thesis highlights two different but complementary approaches to drug discovery. To discover compounds that may be clinically useful in blocking new blood vessel formation (angiogenesis) a library of 270,000 compounds was screened for inhibition of the methionine aminopeptidase 2 (MetAP2) enzyme. Two promising lead compounds were identified that are specific for manganese substituted MetAP enzyme, cause G1/S arrest in endothelial cells, and inhibit angiogenesis in a mouse model.
Although these two lead compounds identified are promising, the de novo drug discovery pathway necessary to bring them to the clinic is lengthy and expensive. To accelerate this process I created a library of 2,687 existing drugs. In a test of concept I screened this library for inhibitors of endothelial cell proliferation and identified three promising compounds: the immune suppressant mycophenolic acid, the ophthalmic antiviral trifluridine, and the antifungal itraconazole. All three compounds reduce in vivo angiogenesis in a mouse model. In T-cells mycophenolic acid inhibits both isoforms of the inosine monophosphate dehydrogenase (IMPDH) enzyme. In this thesis I show, with the assistance of Dr. Fan Pan, that IMPDH-1 plays a crucial role in endothelial cell proliferation while IMPDH-2 is essential for T-cell proliferation. This suggests that IMPDH-1 specific inhibitors may be useful as anti-angiogenic drugs but lack the immunosuppressive side-effects of drugs like MPA that target both isoforms.
The clinical compound library was also screened for inhibitors of the human malaria parasite P. falciparum . A promising compound identified is the non-sedating antihistamine astemizole which inhibits chloroquine-sensitive and -resistant parasites in culture and in three murine malaria models. Like the quinoline antimalarials astemizole reversibly inhibits heme crystallization and co-purifies with heme crystals isolated from parasites. These results suggest astemizole may be a promising new treatment for malaria as it is currently used in 30 countries including malaria endemic areas like Cambodia and Vietnam.
Although de novo drug discovery is an essential part of pharmacology, given the time and expense necessary to find a new drug it may be useful to examine the pharmacopoeia to identify new uses for existing drugs.