May 26, 2020
A. Douglas Kinghorn, BPharm, PhD, DSc, professor and Jack L. Beal Chair of the Division of Medicinal Chemistry and Pharmacognosy at The Ohio State University College of Pharmacy, has received a competitive P01 grant renewal for years 11-15 (2020-2025) of his project, “Discovery of Anticancer Agents of Diverse Natural Origin.” This new award totals more than $7 million and is funded by the U.S. National Cancer Institute, National Institutes of Health.
Operational since 2007, the goal of this integrated multidisciplinary program project is the discovery of compounds from tropical plants, coastal lichens, cultured cyanobacteria and filamentous fungi to serve as anticancer drug leads. The research project group is a collaboration between three primary institutions: The Ohio State University (Ohio State); the University of Illinois at Chicago (UIC); and the University of North Carolina at Greensboro (UNCG).
“My colleagues and I are especially appreciative of this third five-year funding period for our P01 project from NCI, since this will enable us to continue with the substantial momentum that has been established previously,” Dr. Kinghorn said. “Since this multidisciplinary project began, the combined effort of the team has led to over 180 peer-reviewed research and review articles, as well as about 30 PhD dissertations related to the work, with 14 coming from Ohio State thus far. The technical results emanating from this P01 project on natural products from our joint laboratory work have attracted wide scientific attention, with several excellent lead compounds having been obtained.”
Co-investigators from the Ohio State College of Pharmacy include: Esperanza Carcache de Blanco, PhD; Christopher Coss, PhD; James Fuchs, PhD; Mitch Phelps, PhD; H. Liva Rakotondraibe, PhD; and Jack Yalowich, PhD.
“We are very grateful to all those who have been involved. In addition to the participating faculty members from the Ohio State College of Pharmacy, I would like thank Sharyn Baker, PharmD, PhD; Alex Sparreboom, PhD; and Lara Sucheston-Campbell, PhD, for being willing to serve on our Ohio State Internal Advisory Committee. Also serving in this capacity are Drs. John Byrd, Division of Hematology, Ohio State College of Medicine, and Raphael Pollock, director, OSUCCC – James. I would also like to acknowledge, in particular, the Program Grants Development Office of the OSUCCC – James and Joy Scott of the College of Pharmacy business office for the invaluable support received.”
The project has three projects and three cores:
Project 1 – Isolation Chemistry of Tropical Plants and Biological Evaluation
(Ohio State; Project Leader, Dr. A. Douglas Kinghorn)
Project 1 involves the isolation chemistry of bioactive tropical plants to be collected by Project 2 (see below), inclusive of extraction, dereplication, compound purification, structure elucidation and scale-up isolation stages. More recently, work has begun in screening U.S. coastal lichens and their fungal mycobionts (Dr. H. Liva Rakotondraibe). Biological screening is offered for Projects 1-3 using a selection of secondary cell-based and mechanism-based assays (Drs. Esperanza J. Carcache de Blanco and Jack C. Yalowich).
Project 2 – Isolation Chemistry of Cultured Cyanobacteria and Plant Acquisition
(UIC; Project Leader, Dr. Jimmy Orjala)
Project 2 entails cyanobacterial collection, culturing, genomic evaluation (Dr. Alessandra Eustaquio), extraction, and dereplication, as well as plant collections from tropical rainforests (Dr. Djaja D. Soejarto). Extracts from the plants are further investigated in Project 1.
Project 3 – Isolation Chemistry of Filamentous Fungi and Biological Evaluation
(UNCG; Project Leader, Dr. Nicholas H. Oberlies)
Project 3 works on new lead compounds from fungi obtained from Mycosynthetix Inc. (Hillsborough, NC; CEO/CSO Dr. Cedric J. Pearce), and comprises culturing, extraction, dereplication, compound purification, structure elucidation, scale-up isolation/yield optimization and biosynthetic manipulation. Some biological testing is carried out at Columbia University as part of Project 3 (Dr. Brent R. Stockwell).
Core A – Administrative and Biostatistics Core
(Ohio State; Core Director, Dr. A. Douglas Kinghorn)
Core A carries out overall administrative functions (aided by Dr. Amanda S. MacFarlane) and offers biostatistics support (directed by Dr. Xiaoli Zhang) to Projects 1-3 and Cores A, 1, and 2.
Core 1 – Biological Correlation and Analysis Core
(UIC; Core Director, Dr. Joanna E. Burdette, assisted by Dr. Leslie Aldrich)
Core 1 provides in vitro testing (screening assays using a small cancer cell line panel; HDAC and proteasome inhibition assays), for samples submitted by Projects 1-3. Promising compounds are evaluated mechanistically and evaluated in mouse hollow fiber and xenograft bioassays.
Core 2 – Medicinal Chemistry and Pharmacokinetics Core
(Ohio State; Core Director, Dr. James R. Fuchs)
Core 2 conducts medicinal chemistry (synthesis/analogue development, SAR evaluation) and pharmacokinetic-related functions (e.g., solubility, stability, formulation, metabolism, protein binding; supervised by Dr. Mitch A. Phelps and aided by Dr. Chris Coss) for selected compounds of promise from Projects 1-3.
“We are extremely proud of the work that Dr. Kinghorn and his team are doing through this grant,” said Henry Mann, PharmD, FCCP, FCCM, FASHP, dean and professor of the College of Pharmacy. “Our faculty are working tirelessly to advance drug discovery for some of the most pressing medical problems. The work that Dr. Kinghorn has done for the past 13 years is representative of this.”
“This is the only program project from the National Cancer Institute that is led by an investigator in a college of pharmacy,” said Cynthia Carnes, PharmD, PhD, senior associate dean of research and graduate studies at the College of Pharmacy. “It is also one of the longest-running program projects in a college of pharmacy that is funded by the National Institutes of Health, which is indicative of the broad impact of Dr. Kinghorn’s leadership and accomplishments on the field. In addition to scientific impact, this program provides exceptional training for trainees in our college, and I am delighted that the program will be providing further training for another generation of scientists.”