Drug Discovery and Development Shared Resource

University Of Colorado Denver, Aurora CO

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Overview: The Drug Discovery and Development Shared Resource (D3SR) provides infrastructure and expertise for high-throughput and high-content screening (HTS/HCS) against molecular targets and cellular phenotypes that drive cancer progression and metastasis as well as in vitro and in vivo pharmacology studies of novel agents or novel combinations to define pharmacokinetic (PK) and/or pharmacodynamic (PD) parameters. Lead compounds can be further developed through hit-to-lead validation studies and in vivo toxicology and pharmacology studies to define safety and dosing for use in appropriate animal models. In addition, the D3SR incorporates expertise in synthetic medicinal chemistry with access to computational modeling and pathology to optimize and investigate lead compounds, novel targets, and drug combinations associated with cancer therapy. Services: The goal of the D3SR is to facilitate the pre-clinical cancer drug discovery and development pipeline for the UCCC by providing services including assay development, HTS/HCS of drug libraries, lead optimization consultation, in vitro lead prioritization, in vivo pharmacology and pharmacokinetics, and in vivo toxicology. Accessory services include pathology, medicinal chemistry, and computational modeling (e.g. structure-based drug design). Equipment: Our facilities house state-of-the-art equipment and instrumentation, featuring: automated robotics; liquid handling; multiparametric plate readers; Operetta and Opera Phenix HCS systems (PerkinElmer); 3 triple quad mass spectrometers with associated LC systems for LCMS analysis; and a 125,000- compound library of FDA approved drugs, clinically relevant drugs, pure natural products, and drug-like diversity sets. Management: The D3SR is a hybrid SR co-directed by D Gustafson (DT; Flint Animal Cancer Center [FACC], CSU) who oversees the pharmacology services located at CSU; and by D LaBarbera (DT; School of Pharmacy [SOP], UCAMC) who oversees the HTS/HCS services. UCCC collaborates with CSU and SOP on the management of each component. Proposed CCSG funding will represent 25% of the annual operating budget; with the remaining from user fees (54%), and institutional support (21%). Use of Services: Since 2016, 86 investigators (37% UCCC members) have used D3SR to study 27 cancer drugs generating 30 peer-reviewed cancer-related publications. Innovation and Developments: The D3SR is a reimagining of the Pharmacology Shared Resource (PharmSR) that has been in the UCCC SR portfolio for over 20 years and represents an evolution to a comprehensive drug discovery and development resource. Consultation and Education: The D3SR provides consultation and education regarding assay development, chemical libraries, data analysis, and other subsequent studies that are inherent to cancer drug discovery and tailored to UCCC members. Future Directions: The D3SR will expand services into genetically-defined models for studying drug PK/PD as well as HTS genomic screens for synthetic lethality and mechanistic studies of drug action supported by the development of joint protocols with the Genomics and the Functional Genomics SRs.