An innovative proposal to dramatically reduce the cost of drug discovery has won Scripps Research chemist Thomas Kodadek, PhD, one of ten Transformative Research awards from the Director of the National Institutes of Health, Francis Collins, MD, PhD.
Kodadek’s award, worth more than $4 million over five years, is part of an initiative called the NIH Common Fund High-Risk, High-Reward program, which is intended to support unconventional approaches to major challenges in biomedical and behavioral research.
Kodadek’s proposal harnesses the power of scale both large and small. It employs miniaturization technologies developed by Kodadek and others at Scripps Research, reducing the amount, and thus the expense, of compounds required to test drug candidates against cellular targets. It also envisions development of vast “libraries” of millions of biologically important compounds displayed on beads roughly the size of a human cell.
The system would allow millions of different chemical compounds to be tested for their ability to drive a desired change in cells. These might include tests for compounds that interfere with cancer cell proliferation, or compounds that can prevent toxic Alzheimer’s plaques from accumulating in brain cells, Kodadek says.
“If the fundamental problems of high cost and target identification could be solved,
this new type of screening could provide a wealth of drug leads, even for diseases whose mechanisms are not sufficiently well understood to allow standard target-focused screens to be carried out,” Kodadek says.
The platform has the potential to slash drug-discovery costs by 100-fold, he adds. The potential applications go beyond cancer and diseases like Alzheimer’s, and include anti-bacterial agents, since “this system should be especially effective for finding novel compounds toxic to bacterial pathogens,” Kodadek says.
The NIH’s Transformative Research Award was established in 2009 to encourage interdisciplinary approaches to research problems. It funds scientific endeavors that, while inherently risky and untested, “could potentially create or challenge existing paradigms,” the NIH says.
Combining technologies to speed discoveries
Kodadek’s multi-year plan begins by creating the compound libraries, and encoding each chemical structure with a unique DNA segment—not the DNA that makes up human genes, but DNA used as information storage system.
A cell engineered to show the outcome of the test via a fluorescent tag would be pasted to a bead and then suspended in a gel, like stars in a galaxy. Releasing the chemicals from the beads will expose the affixed cells to the chemical on the particle. The cell will glow more or less brightly depending upon the test’s setup. The DNA encoding the chemical “hits” can be sequenced, revealing the structure.
Kodadek says melanoma and pancreatic ductal cell carcinoma will be among the first cancer cells to be screened, with the intent of finding compounds that are selectively toxic to the cancer cells, but not to healthy cells.
Critical to the system, the compounds in the library will be equipped with “weakly reactive electrophiles,” compounds whose charge will drive them to bind to target proteins.
“This tight connection between the active molecule and its target will greatly simplify finding this needle in a haystack,” Kodadek says.
Once the basic platform is established, Kodadek says he plans to make the compound libraries he develops available to collaborators, in the hopes of advancing many areas of biological research.
The NIH Director’s High-Risk, High Reward grants, totaling $282 million over five years, will go to 89 investigators nationwide this year. They include 10 Pioneer, 58 New Innovator, 10 Transformative Research, and 11 Early Independence awards. In addition to the 2018 Transformative Research award, Kodadek in 2006 received the NIH Director’s Pioneer award.
Source : The Scripps Research Institute