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Can protein degraders unlock ‘undruggable’ drug targets?

Exploring a new and exciting area of small-molecule drug discovery

A new class of protein degrader drugs is promising to unlock the large proportion of human proteins that are extremely difficult to target when using conventional small- and large- molecule drugs.

Drug discovery is almost entirely focused on controlling protein activity to treat or cure diseases, using small-molecule or biologics to inhibit or in some cases boost the activity of a target protein.

Stability and delivery problems

One problem with this approach is that protein- targeting drugs generally have to be given in high concentrations to have a potent effect, and that can cause off-target activity that can lead to side effects. Even carefully targeted drugs like nucleic acids pose stability and delivery problems which make systemic delivery a challenge.

Now, interest is growing in a largely-untapped approach to targeting disease-associated proteins, particularly those that for many years have been considered ‘undruggable’. It involves harnessing the cell’s own machinery for selective degradation of proteins implicated in human diseases, and has opened up a new and exciting area of small- molecule drug discovery.

It is estimated that only 25-30% of known cellular proteins can be targeted by current inhibitor drugs, with the remaining 70-75% of proteins regarded as undruggable.

The hope is that selectively degrading abnormal proteins known to be involved in diseases could open up a fertile new drug discovery and development field, and the first targeted drugs that purport to work in this way are already approaching clinical read-outs.

Clinical candidates

US biotech Arvinas – founded by protein degrader pioneer Craig Crews of Yale University – seems to be out in front in the emerging field at the moment, starting a phase 1 trial of its lead candidate ARV-110 in prostate cancer earlier this year, ahead of rival biotechs such as C4 Therapeutics and Kymera Therapeutics as well as big pharma firms like Novartis, Amgen, Pfizer and Merck & Co/MSD.

Novartis is reported to be approaching the clinic with another drug for an as-yet undisclosed therapeutic target, perhaps before the end of the year, while Kymera is gearing up to start initial human testing of its lead candidate KYM-001 in 2020 that is said to have potential in various cancers including a particularly aggressive subset of B-cell lymphoma.

One form of protein degradation involves cellular pathways including the ubiquitin proteasome system (UPS), which plays a central role in maintaining proteins in cells at the correct level. Proteins that are in excess are tagged for destruction – or proteolysis – by attaching ubiquitin to their surface, and that stimulates the activity of enzymes (protein ligases) that break them down.

Another is based on hydrophobic tagging of proteins, which relies on the fact that hydrophobic patches on the surface of protein molecules are an indicator that proteins have become slightly unfolded, and so may be impaired and need to be degraded. Small-molecule probes have been developed that target a protein for destruction.

Double-headed molecules

Latterly, a lot of research effort has gone towards developing proteolysis-targeting chimeras or PROTACs, which are double-headed molecules with one head engineered to bind to the target protein, and the other binding to an E3 ubiquitin ligase.

The molecule recruits the ligase to start the proteolysis process, and it is this mechanism that Arvinas is trying to exploit with its ARV-110 candidate. The bifunctional molecule targets E3 ligase at one end, and the androgen receptor on the other.

In theory, getting rid of the androgen receptor altogether should prove to be a more reliable strategy than current approaches that rely on drugs to remain bound to the receptor to keep it inhibited – and which also run the risk of cancer cells acquiring resistance by developing receptor mutations.

It’s worth mentioning that one drug that works via protein degradation is already on the market, although it isn’t generally billed as working in
this way. AstraZeneca’s injectable drug Faslodex (fulvestrant) for breast cancer has been approved since 2002, and acts by causing the oestrogen receptor to become more hydrophobic and stimulate degradation, rather than simply inhibiting it like other anti-oestrogen drugs.

Arvinas’ next candidate – ARV-471 – intends to go one better, by offering an oral PROTAC therapy that is more effective at depleting the oestrogen receptor. ARV-471 is due to start a phase 1 trial in the third quarter and will be its second clinical candidate.

Disrupting the signal

Kymera’s KYM-001 meanwhile is designed to knock down interleukin-1 receptor associated kinase 4 (IRAK4), thereby disrupting a cancer-promoting signalling pathway known as the myddosome. The company estimates that mutations in the MYD88 gene involved in that pathway are implicated in up to 40% of diffuse large B-cell lymphomas.

Other approaches are also in early-stage testing. Deubiquitylating (DUB) inhibitors are being championed by the likes of Mission Therapeutics and Forma Therapeutics and – rather than using E3 ligases to stimulate degradation – try to block cellular processes that rescue proteins already marked for destruction.

Causing instability

Cedilla Therapeutics meanwhile is taking what it describes as a ‘multi-faceted’ approach to stimulate protein degradation by disrupting the stability of molecules, looking at direct ligand-induced mechanisms as well as upstream regulators that control protein stability and abundance, and ways to disrupt protein-protein interactions that could also activate degradation pathways.

Some groups are focusing on SNIPERs – an acronym for Specific and Non-genetic Inhibitor of apoptosis protein-dependent Protein Erasers
– which work similarly to PROTACs. The appeal also lies in the premise that the only essential requirement is for drugs to bind to a protein, so compounds with no inhibitory activity can be used. These compounds could be used to tackle resistance to kinase inhibitor drugs, for example.

It is early days, and there still big challenges to overcome, say researchers, not least improving the selectivity and speed of binding of small-molecule drugs to their protein targets, and assessing how quickly cells can repopulate knocked-down proteins.

That’s not dampening enthusiasm for the emerging field, however, and by some estimates, just about every big pharma company is active
in this area, either through in-house projects or collaborations with protein degradation specialists.

Big pharma and new start-ups

Arvinas recently attracted a $750m-plus partnership with Bayer to develop PROTAC drugs for cardiovascular and gynaecological diseases and cancer, as well as agricultural products, which adds to previous collaborations with Roche’s Genentech subsidiary, Pfizer, and also Merck & Co/MSD that committed $434m to the company shortly after it launched in 2013. The Merck alliance came to an end last year, but the others remain in place.

In June, Gilead teamed up with Nurix on a project to discover new cancer drugs, paying the biotech $45m upfront to tap into its discovery platform based on ubiquitin proteasome system. The deal could top out at a massive $2.3bn, which gives an indication of the promise that is being attributed to protein degradation in drug discovery.

In 2015, Celgene signed up with Nurix for a project to find drugs that may improve the immune response to cancer. The lead project in that partnership is an inhibitor of CBL-B, an immune checkpoint that is still in preclinical development and will migrate to Bristol-Myers Squibb when its $74bn merger with Celgene goes through later this year.

Kymera has attracted partnerships too, including a two-year alliance with GlaxoSmithKline signed last year that is focusing not only on finding new drug candidates but also new E3 ligases. It raised $30m in its series A in 2017, and followed that up with a second-round fundraising last November that raised $67m and added Pfizer and Sanofi’s venture capital units to its list of investors.

In January, C4 Therapeutics signed a $900m collaboration with Roche for its heterobivalent degrader technology – comprising a ‘target-binding warhead, a linker, and an E3-recruiting ligand’ – upgrading a 2016 alliance between the two companies.

The partners aren’t revealing much detail about the programme, other than to say that it spans multiple disease targets and C4 will take the lead ‘from discovery through defined preclinical or early clinical milestones’. C4 also has a collaboration in place with Biogen focusing on neurological conditions such as Alzheimer’s disease and Parkinson’s disease worth up to $415m.

Meanwhile, new start-ups in the category continue to arrive on the scene. In June, Frontier Medicines launched with $67m in first-round financing and a management team that includes veterans from AstraZeneca and Johnson & Johnson as well as former Arvinas chief scientific officer Jim Winkler, who is heading the new firm’s protein degrader activities.

Article by
Phil Taylor

Phil Taylor is a healthcare journalist specialising in the life sciences industry

26th February 2020

Article by
Phil Taylor

Phil Taylor is a healthcare journalist specialising in the life sciences industry

26th February 2020

From: Research



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