The concept of targeted protein degradation presents revolutionary drug development opportunities and is anticipated to bring about a paradigm shift in modern healthcare. While conventional medicines, such as small molecule inhibitors and monoclonal antibodies, address fewer than 20% of the proteome, targeted protein degradation offers a unique means to tap into the rest of the vast, unexplored proteome.
The science behind this innovation revolves around the use of specially designed small molecules that are capable of recruiting the ubiquitin-proteasome system (UPS) to selectively eliminate a target protein, via proteolysis.
Over the years, significant progress has been made towards understanding the physiochemical and biological properties of these bifunctional molecules. In fact, a variety of other chemical entities and molecular glues have been developed for the treatment of a variety of clinical conditions. The growing popularity and interest in the therapeutic potential of these molecules is evident across modern scientific literature (500+ related articles on NCBI’s PubMed portal), and from social media chatter (4,000+ tweets posted on the platform, Twitter, over the last three years).
Current pipeline of targeted protein degradation-based drugs
During our research, we came across close to 90 targeted protein degradation-based therapeutics that are being investigated for a wide variety of application areas. The first targeted protein degrader, called proteolysis targeting chimera (PROTAC), was developed about a decade ago, and is currently accounting for more than 30% of the pipeline drugs. These are being developed primarily to treat advanced oncological disorders (such as acute myeloid leukemia, breast cancer, lung cancer, multiple myeloma, and prostate cancer). A few drugs are also being evaluated for the treatment of non-oncological indications.
ER+/HER2- is the most popular target protein, as per the current drug development focus in this domain. Specifically, in the clinical pipeline, about 10 drugs are being developed to target ER+/HER2-; examples include (in decreasing order of clinical phase of development) elacestrant (phase III), SAR439859 (phase II), G1T48 (phase I/IIa), LSZ102 (phase I/Ib), ARV-471 (phase I), AZD9833 (phase I), AZD9496 (phase I), D-0502 (phase I), GDC-9545 (phase I) and GDC0927 (phase I).
Most of the molecules that we came across are being evaluated as both monotherapies and combination therapies (56%), whereas around 26% are being investigated as monotherapies alone. Given that majority of the therapeutics are small molecules, the most preferred route for the delivery of targeted protein degradation-based therapeutics is oral route (over 85%), followed by the intravenous route (~11%).
During our research, we came across more than 60 clinical trials that have been registered across different geographical locations for evaluating targeted protein degradation-based therapeutics. Examples of the most active industry players in this domain include (in decreasing order of number of clinical trials) Celgene, Samus Therapeutics, Medivir, AstraZeneca, Radius Pharmaceuticals, Genentech, Sanofi, Arvinas, CellCentric, and InventisBio.
For further information on this emerging domain, check out the report here.