Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 45, Pages 15280-15291Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.014715
Keywords
targeted protein degradation; ternary complex; PROTAC; cooperativity; protein degradation; mathematical modeling; molecular pharmacology; kinetics; E3 ubiquitin ligase; drug development; chemical biology; computational biology; heterobifunctional ligand
Categories
Ask authors/readers for more resources
Small molecule-induced targeted protein degradation by heterobifunctional ligands or molecular glues represents a new modality in drug development, allowing development of therapeutic agents for targets previously considered undruggable. Successful target engagement requires the formation of a ternary complex (TC) when the ligand brings its target protein in contact with an E3 ubiquitin ligase. Unlike traditional drugs, where target engagement can be described by a simple bimolecular equilibrium equation, similar mathematical tools are currently not available to describe TC formation in a universal manner. This current limitation substantially increases the challenges of developing drugs with targeted protein degradation mechanism. In this article, I provide a full, exact, and universal mathematical description of the TC system at equilibrium for the first time. I have also constructed a comprehensive suite of mathematical tools for quantitative measurement of target engagement and equilibrium constants from experimental data. Mechanistic explanations are provided for many common challenges associated with developing this type of therapeutic agent. Insights from these analyses provide testable hypotheses and grant direction to drug development efforts in this promising area. The mathematical and analytical tools described in this article may also have broader applications in other areas of biology and chemistry in which ternary complexes are observed.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available