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Small-Molecule Strategies Aimed at Degrading Cellular Proteins

October 15, 2015

By Garrett Rhyasen, PhD

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After securing a $18.25 million Series A co-led by Canaan Partners and 5AM Ventures in 2013, Arvinas, Inc., has been quietly working on creating a new class of small-molecule drugs. The company was born from the Yale-based research laboratory of Craig Crews. Crews is acclaimed in the world of chemical biology for work which led to the development of the FDA-approved proteasome inhibitor Kyprolis. The Arvinas secret sauce relies on re-directing the cell’s protein-degradation system (i.e. E3 ligases) against protein targets. The so-called bivalent Proteolysis-Targeting Chimeras (PROTAC) can be deployed against protein targets to induce proteosome-mediated degradation. Importantly, this approach potentially allows for the targeting of intractable protein targets.


Arvinas PROTAC technology results in target protein degradation

The recently discovered molecular mechanism of lenalidomide, Celgene’s blockbuster immunomodulatory drug, provides a great illustration on how PROTAC technology works. Back in the late 90’s thalidomide, a cousin to lenalidomide, first demonstrated remarkable anti-cancer activity. Today lenalidomide (Revlimid) is approved for use in Multiple Myeloma and del(5q) Myelodysplastic Syndrome. For decades scientists have sought to understand the anti-cancer mechanism employed by this drug class. Early illustrations of mechanism involved hand-waving generalizations including, but not limited to, paracrine/autocrine interactions between myeloma cells and surrounding stroma, regulation of cytokine expression, and regulation of oxidative stress. At some point (and long before IO was in vogue), people began using the immunomodulatory (IMiD) label to describe thalidomide analogs. Nonetheless, such broad explanations for drug activity aren’t particularly helpful when looking to assess modern clinical parameters such as target exposure, target engagement, and modulation of downstream pharmacodynamic markers. The granular understanding of how these agents really work was catalyzed by a seminal discovery in 2014. The crystal structure of human Cereblon-DDB1-lenalidomide was solved and published in Nature Structural Biology. Cereblon is a E3 ubiquitin ligase, so it was not immediately clear how Cereblon engagement via lenalidomide could exert such pleiotropic immune effects. Using proteome-wide ubiquitination analyses two independent groups demonstrated that lenalidomide binds Cereblon and alters its E3 ligase substrate specificity against two B cell Ikaros transcription factors (IKZF1/3) inducing their degradation (Figure 1 and see the original research findings here and here). The anti-cancer and immunomodulatory effects of lenalidomide emerge from destruction of IKZ1/3 in tumor cells, resulting in decreased MYC and IRF4 expression. Additional immune effects are mediated through the activation of T cells through upregulation of IL2.


PROTACs provide a potency advantage of traditional small molecule inhibitors

The Arvinas PROTAC technology relies on bi-functional molecules as shown in Figure 2. In this example, a BRD4 inhibitor is connected to a thalidomide analogue via a chemical linker. The bi-functional nature of this molecule allows ligation of the E3 ligase Cereblon to BRD4, and subsequent Cereblon-mediated BRD4 degradation via addition of ubiquitin to available lysine residues on BRD4. The BRD4 PROTAC, ARV-825, is quite potent, and capable of BRD4 degradation at nM doses (Figure 2).  Typical run-of-the-mill BRD4 inhibitors such as the tool compound JQ1 or the clinical candidate OTX015 (written about in a previous Oncology Discovery post here) conversely can result in upregulation of BRD4 (as shown in Burkitt’s Lymphoma lines in Figure 2). Moreover, ARV-825 is capable of more potently inducing the downregulation of MYC, a downstream effector of BRD4 in this setting, and more potently inhibits proliferation in these cells.

Jay Bradner, Dana-Farber physician-scientist and soon to be Novartis R&D Chief, published a recent manuscript in Science demonstrating the advantages of a similar approach, which uses the BET bromodomain inhibitor JQ1 linked to a thalidomide analogue. The language in a related Dana-Farber press release suggests that Jay’s group will seek to file IP in this area. This could signal the emergence of future competition, but at least for now Arvinas is leading in their approach.


PROTACs circumvent known resistance mechanisms

The promise of the Arvinas degradation platform extends beyond simply creating more potent drugs. In addition to BRD4, Arvinas has generated PROTACs against androgen receptor (AR). Interestingly, the AR PROTACs appear to be meaningfully differentiated from Medivation’s enzalutamide (Xtandi) (Figure 3). Unlike enzalutamide, the AR PROTAC is able to sustain an anti-proliferative effect in prostate cancer cell lines in the presence of exogenous androgen, is active against clinically relevant AR mutations (including AR-F876L), and does not display agonist-like properties against AR-F876L.

In 2015 Merck and Genentech have taken notice

Arvinas hasn’t gone unnoticed by Biopharma — in fact, 2015 has proven to be a banner year for the company. In April of this year Arvinas announced a strategic collaboration with Merck for an undisclosed up-front payment and $434M in milestones to study the platform on multiple disease targets across several therapeutic areas. In similar fashion, earlier this month Genentech inked a strategic agreement with Arvinas for an undisclosed up-front payment and up to $300M in milestones. Along with the scientific pedigree of the company these deals serve to provide additional validation to the Arvinas degrader technology.

Exciting future applications

One of the most exciting applications of this technology lies in targeting currently intractable targets. There are several potential approaches here; I’ll explain an obvious example. The catalytic subunits of the SWI/SNF complex (SMARCA4 and SMARCA2) are frequently mutated in cancer. They function as mutually exclusive subunits. A cancer-specific synthetic lethality can be exploited in malignancies where one subunit is lost to mutation. For this reason, drug hunters have taken aim at developing SMARCA2/4 inhibitors for use in SMARCA2/4-mutant cancers. In fact, Pfizer chemists, in collaboration with the SGC, created PFI-3, a selective probe for SMARCA4. Unfortunately, the phenotypic effects of PFI-3 against SMARCA2-mutant cancer cells have been disappointing. So what gives? Well, PFI-3 is a SMARCA4 bromodomain inhibitor, and it turns out SMARCA4-bromdomain inhibition is insufficient to abrogate SMARCA4 catalytic function. The Arvinas platform could potentially solve the problem of generating a potent SMARCA4 inhibitor through linking a PFI-3-like molecule to a thalidomide analogue. The resulting ‘PFI-3-thalidomide PROTAC’ could ostensibly result in SMARCA4 degradation and thus provide a suitable drug to enable synthetic lethality in SMARCA2-mutant tumors.

Key competitive advantages of the PROTAC platform versus traditional medicinal chemistry approaches:

  • Increased drug potency
  • Overcome the requirement for large systemic drug concentrations, and continuous drug exposure
  • Circumvent drug resistance mechanisms
  • Approach intractable targets using target-binding ligands that lack target inhibitory activity (e.g. ligands for transcription factors and other protein-protein interactions)

As always, if you have any questions or comments feel free to reach out to me on Twitter or via email at

Publicly traded companies mentioned: Celgene (CELG), Medivation (MDVN)

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