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Principal Investigator: Jae-Yeon Choi
Organization: CURATIX, LLC
Fiscal Year: 2024
Award: $300,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <A fumigatus><A. fumigatus><Address><AmB><AmBisome><Amphocil><Amphotec><Amphotercin B><Amphotericin B><Anabolism><Animal Model><Animal Models and Related Studies><Aspergillosis><Aspergillus><Aspergillus fumigatus><Azoles><Baker's Yeast><Binding><Biochemical><Biological><Brewer's Yeast><C albicans><C. albicans><C. glabrata><C.albicans><Candida><Candida albicans><Candida glabrata><Candidiasis><Candidosis><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Survival><Cell Viability><Cessation of life><Chemicals><Clinical><CoA><Coenzyme A><Complex><Cryptococcus><Data><Death><Death Rate><Development><Development and Research><Disseminated candidiasis><Disseminated candidosis><Dose><Drug Kinetics><Drug resistance><Drugs><Economic Burden><Economics><Enzyme Gene><Enzymes><Ergosterol><Fluconazole><Fungizone><Fungus Diseases><Generations><Genetic study><Goals><High Throughput Assay><Hospital Infections><Hospital acquired infection><Hospitals><Human><Human Cell Line><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Infection><Lead><Length of Stay><Libraries><Lytotoxicity><Manuscripts><Maps><Medication><Medicinal Chemistry><Metabolic><Metabolic Pathway><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monilia><Moniliasis><Morbidity><Morbidity - disease rate><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mycoses><Mysteclin-F><Nosocomial Infections><Number of Days in Hospital><Oral><Organism><Pantothenate kinase><Pantothenic Acid><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Permeability><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacokinetics><Pharmacological Study><Pharmacology Study><Phase><Phosphorylation><Pneumocystis><Polyenes><Property><Protein Phosphorylation><Public Health><R & D><R&D><Regimen><Relationship-Building><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><S cerevisiae><S. cerevisiae><Saccharomyces cerevisiae><Safety><Solubility><Structure><Structure-Activity Relationship><Systemic candida><Systemic candida infections><Systemic candidiasis><Therapeutic Fungicides><Torula><Torulopsis glabrata><United States><Vitamins><analog><anti-fungal><anti-fungal agents><anti-fungal drug><biologic><biosynthesis><chemical structure function><cofactor><cytotoxicity><determine efficacy><developmental><diflucan><drug resistant><drug/agent><economic><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><fungal infection><fungal pathogen><fungi pathogen><fungus><fungus infection><healthcare burden><heavy metal Pb><heavy metal lead><high throughput screening><hospital days><hospital length of stay><hospital stay><immunosuppressed patient><improved><in vitro activity><in vivo><indexing><inhibitor><institutional infection><kinase inhibitor><lead candidate><living system><meter><model of animal><monomer><mortality rate><mortality ratio><mouse model><multi-drug resistant><multidrug resistant><murine model><new drug class><novel><novel drug class><pantothenate><pathogen><pathogenic fungus><pathway><patient oriented outcomes><pharmacologic><programs><research and development><resistance strain><resistance to Drug><resistant><resistant strain><resistant to Drug><scaffold><scaffolding><screening><screenings><structure function relationship><therapeutically effective><treatment strategy>