Antifungals targeting pantothenate phosphorylation

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SUMMARY Invasive fungal infections (IFIs) create significant healthcare and economic burdens as they are responsible for more than one billion infections worldwide each year resulting in more than 1.5 million deaths. Hospital patients who acquire nosocomial IFIs experience longer hospital stays, increased morbidity, and higher mortality rates. Only a few classes of antifungal drugs are available, and the emergence of resistance within all classes is an alarming threat to global public health. Of particular concern are infections caused by Candida, Aspergillus, Cryptococcus, and Pneumocystis species due the level of resistance seen with these pathogens and the associated mortality rates. New classes of anti-fungals are desperately needed, particularly with the emergence of multidrug resistant strains. To address this need, Curatix is developing a new class of anti-fungals that disrupt an essential metabolic pathway and first step in coenzyme A (CoA) biosynthesis - the phosphorylation of vitamin B5 by pantothenate kinase (PanK). Genetic and pharmacological studies demonstrated that in fungi, this step is essential for cell viability, thus validating fungal PanKs as excellent targets for the development of new classes of antifungal drugs. To achieve this goal, we conducted high-throughput screen of ~156,593 compounds to search for inhibitors of A. fumigatus AfPanK and identified three 1st generation compounds within a single chemotype with Ki values ranging between 190 and 360 nM. Screening and preliminary medicinal chemistry optimization of 86 analogs identified four 2nd generation compounds with improved activity against AfPanK as well as S. cerevisiae PanK (Cab1) with Ki values ranging between 12 and 170 nM for Cab1 and 50 and 217 nM for AfPanK. The compounds showed no cytotoxicity against five human cell lines, very high selectivity for fungal PanKs over human PanKs (EC50 >10 µM), and significant biological activity in vitro against C. albicans, C. parapsilosis and C. glabrata. We further solved the crystal structure of Cab1 as an apo-enzyme and in complex with these inhibitors. This Phase I program will build upon these significant data with the goal to evaluate the biological activity of these lead compounds in vivo and initiate an SAR to improve their antifungal potency (>10 fold). In Aim 1 we will characterize the in vivo efficacy of these compounds in animal models of candidiasis and aspergillosis. In Aim 2, we will build upon the biological, biochemical and structural data to generate a library of analogs in order to identify compounds with more potent activity against multiple fungal pathogens. Successful completion of the Phase I program will provide the critical data needed to support a Phase II program focused on the efficacy of the lead compounds in various models of fungal infections alone or in combination with other known antifungals. Clinical use of a PanK inhibitor has the potential to provide a more effective therapeutic option for treating IFIs, both as monotherapy and in combination with existing drugs, thus greatly decreasing the economic and healthcare burdens associated with these infections and improving patient outcomes.