R01AI162789

Targeting the Casein Kinase 1 (CK1)-like Kinase Yck2 in Fungal Pathogenesis - Summary/Abstract

Fungal pathogens have an enormous impact on human health worldwide. In the U.S. alone, bloodstream infections have increased by over 200% in recent decades, associated with an increasing number of people with compromised immune function due to treatment for cancer, organ transplantation, and HIV.

Poor clinical outcome for most invasive fungal infections is attributable to the very limited number of effective antifungals available and the emergence of clinical resistance to each of the three main modes of action they target. Protein kinases have emerged as richly rewarding targets in the development of drugs for diverse diseases, ranging from cancer to metabolic disorders, but kinases as a class have remained completely untapped in the quest for new antifungals.

To begin to fill this void, we tested a panel of well-characterized, structurally diverse kinase inhibitors for activity against a drug-resistant isolate of Candida albicans, the most common human fungal pathogen. This screen identified several compounds which were active against C. albicans and the emerging pathogen, Candida auris.

Using chemical genomic approaches, we established the primary target of our most active compounds as Yck2, a fungal member of the widely expressed casein kinase 1 (CK1) family. Using genetic techniques, we confirmed that Yck2 is required for growth in culture under host-relevant conditions, is required to maintain echinocandin-resistance in culture, and enables the virulence of echinocandin-resistant C. albicans in both immune-competent and immune-compromised mice.

Now, we will exploit selectivity handles revealed by co-crystal structures of the Yck2 kinase domain in complex with our lead and several other inhibitors to optimize potency, fungal selectivity, and pharmacological properties. Pursuing two scaffolds in parallel as a de-risking strategy, our goal is to deliver one or more advanced leads for future development of a clinical drug candidate.

To achieve this goal, our multidisciplinary team will use its expertise in chemistry, structural biology, pharmacology, and fungal biology to pursue the following aims:

AIM 1: Structure-enabled synthesis of Yck2 inhibitors with improved antifungal activity

AIM 2: Optimize cellular and whole animal pharmacology of fungal Yck2 inhibitors

AIM 3: Evaluate tolerability and efficacy in mouse models of systemic fungal infection by drug-resistant clinical isolates with and without concurrent sub-therapeutic echinocandin treatment

The Yck2 inhibitors we develop in achieving these aims are expected to possess single agent activity in vivo as well as reverse/prevent resistance to echinocandins. The development of these compounds will be invaluable not only from the perspective of establishing a new target space for discovery and development of mechanistically distinct single-agent antifungals but also in pioneering a resistance-aversive combination approach to antifungal therapy that has proven essential in controlling other infectious diseases.

The Governing Council Of The University Of Toronto

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Canada

Foreign

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 395% from $625,937 to $3,099,005.