Some of the most important targets in cancer, including KRAS and MYC, have thwarted the best efforts of drug developers for decades because their active sites are not amenable to targeting with small molecule inhibitors. Such proteins have become notorious for this “undruggability” yet remain an area of intense focus for drug development because of their therapeutic potential.
Now there is hope on the horizon that small molecules can, after all, target the undruggable. Recent years have witnessed the rise of an exciting new modality – targeted protein degradation (TPD) – that has attracted some $3 billion in investments to date. This technology holds promise for treating cancers and numerous diseases by targeting proteins that have otherwise proved problematic for conventional small molecule inhibitors.
Unlike inhibitors, targeted protein degraders do not simply block the enzymatic or signaling activity of their targets; they harness the ubiquitin-proteasome system within cells to degrade and clear unwanted proteins. The first small molecule designed to hijack this system – dubbed a proteolysis targeting chimera (PROTAC®) – was reported in 2008 and Arvinas Inc. was founded in 2013 to further develop this technology.
A PROTAC molecule consists of two ligands joined by a linker: one ligand binds the target protein; the other binds an E3 ubiquitin ligase, a key component of the ubiquitin-proteasome system. Once a trimer complex of target, PROTAC, and E3 ligase forms, the ligase tags the target protein with a chain of ubiquitin molecules, marking it for proteasomal degradation.
Since Arvinas was founded, several other biotechs and pharmas have entered the TPD space. While they differ in specifics, most of these companies are pursuing the same principle of hijacking the ubiquitin-proteasome system to eliminate a protein of therapeutic interest.
Modes of Action
The novel mode of action of PROTAC molecules differentiates them from conventional inhibitors in several ways.
First, a PROTAC molecule need not bind a target’s active site. It can be designed to bind any tractable binding site or pocket on the protein, which could allow the molecule to bypass the resistance mechanisms the target may develop to conventional therapies.
Second, a PROTAC molecule does not need to tightly bind its target. This is because the PROTAC molecule’s action of facilitating the formation of the trimer complex, not the strength of its target binding, is the key aspect of its degrading activity. (Published studies have shown a PROTAC molecule bound its target with micromolar affinity yet degraded that target with nanomolar potency.)
Third, PROTAC molecules do not have to maintain target occupancy to be effective. Instead, after the PROTAC molecule has facilitated activation of the ubiquitin-proteasome system, it can disengage from its target and can begin the process anew on another copy of the target protein, over and over. Through this “catalytic” activity, a single PROTAC molecule can degrade hundreds of copies of its target protein. This could translate to lower dosing and/or drug exposures and better safety profiles over conventional inhibitors, though more data are needed to draw definitive conclusions.
Drugging the “Undruggable”
I was first drawn to PROTAC protein degraders by their ability to target undruggable proteins. About 80% proteins fall into this category; many play critical roles in cancer and other diseases. Some, such as the notorious oncoprotein KRAS, are difficult to drug because their active sites are broad, shallow pockets that are challenging to bind with small molecules. Others, such as the transcription factor MYC, which is implicated in up to 70% of all human cancers, offers few nooks for a small molecule to adhere. The potential of PROTAC technology to target these elusive proteins should prove to be its most powerful characteristic in the long run.
However, PROTAC molecules have advantages against other target types as well, such as scaffolding proteins, over-expressed proteins, protein aggregates, and mutated proteins. Scaffolding proteins simultaneously bind one or more other proteins to form a complex. These include transcription factors such as BCL6, which is implicated in B cell lymphomas. Small molecules that inhibit only the transcription or kinase activity of a protein miss its important scaffolding functions; PROTAC molecules could disable those functions.
PROTAC molecules can also target proteins that are overexpressed in a disease. This often occurs in cancers, which can develop resistance to a therapy by upregulating the drug’s target, eventually rendering the drug ineffective. The novel “iterative” or “catalytic” mode of action of PROTAC molecules readily degrades the excess protein, bypassing these resistance mechanisms.
Protein aggregates, especially aggregates of tau, alpha-synuclein, and other proteins involved in neurodegeneration, comprise another target class where PROTAC protein degraders have great potential. Antibodies can target aggregates but are difficult to shuttle across the blood-brain barrier (BBB) and can only target extracellular aggregates. But PROTAC molecules, when designed to do so, readily cross the BBB and enter cells, where they can dispose of the aggregate “at the source”. This could be advantageous because destroying aggregates earlier in the course of the disease likely will be key to treating neurodegenerative diseases.
Finally, because their action depends on the trimer complex, PROTAC molecules can be more selective for their targets than their binding affinities might suggest. This could enable the design of PROTAC molecules that selectively target disease-driving mutant proteins – huntingtin in Huntington’s disease, BRAF mutations in cancer, etc. – without targeting their wild-type counterparts. Alternatively, a PROTAC molecule can be engineered to degrade a mixture of wild-type and mutant forms of a protein, as does ARV-110, a clinical-stage PROTAC molecule that targets wild-type androgen receptor and many of its resistance-driving point mutations.
The PROTAC Promise
This range of targeting options makes PROTAC protein degraders therapeutically agnostic with broad applications to disease. While the first PROTAC molecules to reach the clinic are in cancer indications, other preclinical programs across the industry are exploring the technology’s potential in neurology, immunology, and infectious disease.
One drawback of PROTAC protein degraders is their size: they are larger than many conventional small molecule drugs, and so violate Lipinski’s “Rule of Five” for drug-like molecules. However, PROTAC molecules have been described as “chameleonic” because they can behave “smaller” than they are. Despite their size, they can be designed to have good oral availability and BBB penetrance; as ARV-110 and ARV-471 have shown, their molecular weight does not limit their inherent potential as drugs.
The biopharma industry has recognized the promise of PROTAC protein degraders, spurring several collaborations and partnerships over the past few years: C4 Therapeutics and Roche, Nurix Therapeutics and Sanofi, Kymera Therapeutics, and Vertex Pharmaceuticals, to name a few.
While the novel science behind TPD is fascinating, even more exciting is its potential to target as yet recalcitrant disease-causing proteins and provide therapeutic benefits to millions of patients. New PROTAC protein degraders poised to enter clinical testing will further explore the safety, efficacy and pharmacodynamics of this new modality and, I believe, begin to deliver on its promise across multiple diseases.
Ian Taylor, PhD ([email protected]), is the Chief Scientific Officer of Arvinas based in New Haven, CT.