2024: First PROTAC Enters Phase III Trials (2024)
In 2024, ARV-471 (vepdegestrant), a PROTAC (PROteolysis TArgeting Chimera) degrader of the
oestrogen receptor alpha (ERα) developed by Arvinas in collaboration with Pfizer, entered
global Phase III trials (VERITAC-3) for ER-positive, HER2-negative metastatic breast cancer,
marking the first Phase III evaluation of a PROTAC in any indication. The milestone validated
the targeted protein degradation paradigm as clinically mature and commercially viable, more
than 20 years after the concept was first proposed by Craig Crews at Yale University and
Raymond Deshaies at Caltech in 2001.
PROTACs are heterobifunctional small molecules containing three components: a ligand for the
target protein of interest (the "warhead"), a linker of defined length and flexibility, and a
ligand for an E3 ubiquitin ligase. Upon simultaneous binding of both proteins, the PROTAC acts
as a molecular glue that brings the target into proximity with the ubiquitination machinery,
resulting in polyubiquitination and proteasomal degradation. Critically, the PROTAC molecule
itself is recycled after each degradation event—functioning sub-stoichiometrically—and can
achieve target knockdown approaching genetic silencing levels.
The therapeutic advantages over conventional occupancy-based inhibitors are significant: PROTACs
can degrade mutant, constitutively active, or resistance-conferring forms of a protein that are
difficult to inhibit with ATP-competitive or allosteric approaches; they eliminate all protein
functions including scaffolding and non-enzymatic roles; and their activity depends on ternary
complex formation rather than sustained occupancy, potentially enabling lower doses and reduced
off-target effects.
Phase II data for vepdegestrant presented at ASCO 2024 showed clinical benefit rates of 40–47 %
in heavily pretreated ER+/HER2− metastatic breast cancer, including in patients harbouring
ESR1 mutations conferring resistance to prior endocrine therapies, supporting the Phase III
programme.
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The first PROTAC to enter Phase III trials represented the clinical validation of targeted protein
degradation as a therapeutic modality distinct from enzymatic inhibition, expanding the druggable
proteome to include transcription factors, scaffolding proteins, and other targets previously
considered undruggable. The PROTAC platform offers a potential solution to resistance arising from
target mutation or overexpression and may ultimately enable systematic attack on formerly intractable
oncogenic drivers.