When:
Monday, October 24, 2022
3:00 PM - 4:00 PM CT
Where: Ward Building, Room 5-230, 303 E. Chicago Avenue, Chicago, IL 60611 map it
Audience: Faculty/Staff - Student - Public - Post Docs/Docs - Graduate Students
Contact:
Nate Will
(312) 503-4892
Group: Department of Pharmacology Seminars
Category: Lectures & Meetings, Academic
"Rescuing destabilized protein mutants using small molecules."
Clinical genetics points to many human diseases for which the underlying pathology can be traced to mutations that map to the interior of a folded protein: we hypothesize that these mutations act by destabilizing an otherwise folded protein, such that the protein loses activity because an insufficient amount of the cellular population is correctly folded. However, extant drug discovery expertise is centered around inhibitors of enzyme activity and modulators of cell surface receptors, leaving our community ill-equipped to tackle the challenge of designing compounds that restore the function of proteins deactivated in this manner.
The Karanicolas group has been developing computational tools specifically catered to the shallow surface pockets typical of sites that are not naturally evolved for small-molecule binding. We have recently applied these tools to identify novel druggable sites on the surfaces of two different tumor suppressor proteins, and we identified small drug-like molecules that bind to these sites. By treating cancer cell lines that harbor these mutant tumor suppressors with the corresponding stabilizers, we find that these compounds refold these destabilized mutant proteins and restore WT activity.
We anticipate that the compounds described here may serve as a starting point for new classes of cancer therapeutics. More broadly, however, these represent first proof-of-concept for a new therapeutic modality: using small molecules to revert loss-of-function induced by mutations that act by disrupting protein stability.
John Karanicolas, Ph.D.
Professor of Molecular Therapeutics
Fox Chase Cancer Center