Abstract
Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought ‘undruggable’ targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition. Despite this, many existing drug design and optimization regimens still fixate on binary target engagement, in part due to limited structural data on ternary complexes. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein–protein interactions and intramolecular contacts to the mode of action of this class of compounds. These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling.
Highlights
Following ternary complex formation, it is expected that the target will be ubiquitinated and targeted to the proteasome for degradation
These processes can be monitored through a variety of biochemical approaches, including mass spectrometry and Western blot assays following treatment of cells with PROTACs in the presence and absence of inhibitors of ubiquitination and the proteasome
Establishing a link between ternary complex formation and degradation is warranted, as it illustrates the importance of PROTAC geometry and the orientation of the proteins relative to one another
Summary
Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Recent crystal structures of protein complexes mediated by degrader molecules, including the first PROTAC ternary complex, underscore the importance of protein–protein interactions and intramolecular contacts to the mode of action of this class of compounds These discoveries have opened the door to a new paradigm for structure-guided drug design: borrowing surface area and molecular recognition from nature to elicit cellular signalling. Amongst the first PROTACs to make use of these non-peptidic VHL ligands – MZ1 (first VHL-based BET degrader disclosed in 2015 by the Ciulli Lab [49], see Figure 3B) and ARV-771 (2016, from Yale spin-off Arvinas [50]) – were conjugates of JQ1, a pan-selective c 2017 The Author(s) Could highly potent PROTACs be designed to be active in cells at concentrations that were orders of magnitudes lower than the binary binding affinities of the constitutive warheads, but they could exhibit exquisite target degradation selectivities
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