Advances: Protein degraders as a therapeutic modality
Molecular glues are promising pharmaceuticals for targeted protein degradation
The “Advances” series of articles discuss technological breakthroughs in the life sciences. These articles present important findings from scientific studies and other resources.
Contributing writer
This article was created through equal contributions by Mike V. Van and Vandon T. Duong. Mike is a graduate student in Biology at Stanford University. He received his BS in Biochemistry & Molecular Biology at UC Davis and is currently doing research in the field of epigenetics. If you are interested in being a contributing writer on the Ergo Bio Insights newsletter, please reach out!
Highlights and takeaways
Molecular glues like PROTACs have gained considerable excitement as a therapeutic modality. Rather than inhibition of protein activity, which can be suboptimal, these drugs facilitate the elimination of aberrant proteins with the proteasomal pathway.
Arvinas is leading in the clinical development of protein degraders, with others like Kymera Therapeutics, Nurix Therapeutics, and C4 Therapeutics.
Alternative methods of protein degradation are emerging, including those ligating complexes in the lysosomal pathway or using genetic engineering to enable switchable expression.
Molecular glues for modulating protein expression
Aberrant protein expression often drives disease pathogenesis in, for example, cancer. Overexpression can be corrected by gene silencing, but methods to efficiently deliver antisense oligonucleotides and other nucleic acid therapies are limited. Moreover, these can be quite expensive to manufacture. Small molecules are attractive as drugs due to ease of delivery and affordable manufacturing. Thus, small molecules for ligating degradation complexes to protein targets as an approach to controlling its expression is clinically and commercially tractable. These molecules are often described as “molecular glues”.
Thalidomide is a historical example of a drug that engages degradation complexes (ref). Around the late 1950s, thalidomide was commercialized by Chemie-Grunenthal as a treatment for morning sickness in pregnant women, but later found to cause serious birth defects. Despite its teratogenicity, decades later Celgene Corporation repurposed thalidomide for treating leprosy and multiple myeloma. Contingent on FDA approval was establishing a system for thalidomide education and prescribing safety (STEPS) to limit authorized prescribers and pharmacies, maintain a patient registry, provide patient education for drug-associated risks, and provide periodic pregnancy testing. In 2010, cereblon (CRBN), a component of an E3 ubiquitin ligase complex, was finally identified as the primary binding target of thalidomide (ref). Through its interaction with CRBN, thalidomide induces targeted degradation of zinc finger transcription factors (ref). While the mechanism of action for thalidomide and its derivatives were being slowly unravelled, other groups had purposefully developed molecular glues for localizing protein targets to ubiquitin ligase.
Source: Sakamoto et al. 2001
Proteolysis targeting chimera (PROTAC) was first described two decades ago as a modality to ligating proteins to E3 ubiquitin ligases via small molecules (ref). PROTACs are designed as two-headed small molecules connected together by a linker. One end selectively binds to a target protein while the other end recruits E3 ubiquitin ligase. Once in proximity to the target protein, the E3 ubiquitin ligase tags the target for destruction via the proteasome. This technology has the potential to enable pharmacological targeting of “undruggable” proteins, of which many are responsible for drug resistance in cancer. Instead of inhibiting protein function, PROTACs suppress cancer signaling by driving protein degradation.
PROTACs were first demonstrated with ligating proteins to Skp1-Cullin-F box complex (SCF), but have since been extended to other E3 ubiquitin ligases like Von Hippel-Lindau (VHL) (ref). PROTACs can also be developed by reformatting suboptimal small molecule inhibitors, for example the BET bromodomain inhibitor OTX015 (MK-8628) (ref). OTX015 does not completely suppress the downstream expression of c-MYC or cancer proliferation. This inhibitor can be connected to pomalidomide, a cereblon ligand, to create ARV-825, and this more efficiently suppresses MYC-driven cancers (ref). Of course, the modularity of PROTACs allows for other BET inhibitors to be fused to ligands recruiting other E3 ubiquitin ligases (ref).
Commercial prospects for molecular glues in cancer and other indications
Since the first report of PROTACs in 2001, Craig Crews and his colleagues have gone on to found Arvinas in 2013. Arvinas is developing PROTACs for diseases in oncology and neuroscience, with two programs in clinical trials: a PROTAC for androgen receptor (ARV-110) and a PROTAC for estrogen receptor (ARV-471). Back in October 2019, Arvinas presented preliminary safety, tolerability, and pharmacokinetic data on these two phase 1 programs (ref). Both drugs were shown to be well-tolerated and displayed no dose-limiting toxicities, reaching exposures in humans that were predicted in preclinical studies to have anti-tumour activity. Over a year later in December 2020, Arvinas announced promising early efficacy data on these two drugs in patients with refractory breast or prostate cancer (ref).
Source: Arvinas corporate presentation
ARV-110 did particularly well in a small group of genetically-defined prostate cancer patients, reducing prostate-specific antigen (PSA) levels by >50% in two out of five patients. In addition, patients with wild-type androgen receptor (AR) had PSA reductions of >50%. As for the breast cancer program ARV-471, the estrogen receptor (ER) degrader stopped tumor growth in five of twelve patients (42%) with metastatic ER-positive, HER2-negative breast cancer. These preliminary results generated significant excitement about the PROTACs technology. This news caused the share price to jump from $29.93 (12/11) to $58.38 the next day (12/14) and $74.25 the following day (12/15). Arvinas is now expanding into additional studies for both of their programs, including a phase 1b study of ARV-471 in combination with palbociclib (Ibrance), an approved CDK4/6 inhibitor.
Source: Arvinas corporate presentation
With another 10 internal programs in discovery or in preclinical stages, Arvinas has just shown early promise in their technology platform. Moreover, all these programs are wholly-owned. Arvinas has target discovery deals with Genentech, Pfizer, and Bayer, and is exploring the application of PROTACs in agriculture with Oerth Bio (and jointly with Bayer) (ref). In contrast to treating human patients, Oerth Bio is developing protein degraders to protect crops.
Highly competitive landscape of protein degraders
Other companies that are approaching the clinic with protein degraders include Kymera, C4 Therapeutics, and Nurix Therapeutics. In addition to this, there are early-stage, private companies pursuing their own technology in this space, such as Amphista Therapeutics, Captor Therapeutics, and PolyProx Therapeutics. Many of these companies have molecular glue programs for ligating cereblon, possibly due to the extensive clinical data available on thalidomide and its analogs.
Source: Kymera corporate presentation
The publicly-traded companies with a core technology in molecular glues are valued in the billions. Arvinas, C4 and Nurix have drug candidates in early clinical trials. Surprisingly, Kymera has yet to enter the clinic (expecting to 1H of 2021) but currently has a higher valuation than C4 and Nurix. This could be partly attributed to the Pegasus discovery platform, which includes extensive expression profiles on 600 E3 ligase and multiple targets (ref). Nurix has proprietary DNA-encoded libraries to combinatorially discover and optimize molecular glues (ref). C4 has an open-source system called Achille’s TAG (aTAG), which can be fused to any protein of interest to study targeted degradation with a single molecular glue (ref).
New methods for controlling protein expression
Source: Ding et al. 2020
Instructing proteins to be degraded via the proteasomal pathway is promising for ameliorating disease, but it depends on the expression levels of E3 ubiquitin ligases. For example, if a cancer cell develops attenuated expression of E3 ubiquitin ligases, then PROTACs may be rendered useless and the afflicted patient becomes refractory. The lysosomal pathway is an alternative degradation process that could be leveraged. Like PROTACs, small molecules for mediating protein degradation can be devised in the form of lysosome targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), or autophagosome-tethering compounds (ATTECs) (ref).
Source: Natsume and Kanemaki 2017
Genetically-encoded systems for regulating the expression of synthetic proteins have been recently designed (ref). For example, small molecule assisted shutoff (SMASh) is an approach to control protein expression using a self-excising degron (ref). This tag consists of a protease that removes the degron unless it is inhibited, thereby modifying whether the protein of interest is to be degraded. Split ubiquitin for the rescue of function (SURF) is another distinct method for controlling protein expression (ref). Complementation of a split ubiquitin is driven by chemically-dimerized domains, and this enables switchable cleaving of a degron by ubiquitin-specific proteases. Compared with branched ubiquitins that mark proteins for degradation, ubiquitin attached in linear fashion are specifically cleaved. Note that the SMASh and SURF techniques have opposite effects upon induction by small molecule drugs. In addition, there are tunable destabilization domains, such as DHFR (ref), that can be used to chemically rescue protein from degradation via N-terminal ubiquitination (i.e. the N-end rule).
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Ergo Bio closely follows innovation in the biotechnology space and evaluates interesting drugs and deals. It is run by Vandon T Duong (LinkedIn), feel free to connect! I am a biotech enthusiast and a molecular engineer by training. I am also an avid consumer of news and research around precision medicine.
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