A few days ago, Arvinas, which is committed to developing targeted protein degradation therapies, announced at the American Association for Cancer Research (AACR) annual meeting the molecular structure and pharmacochemical optimization process of two PROTAC based therapies entering the clinical phase. Arvinas' ARV-110 and ARV-471 are PROTAC molecules that respectively target the degradation of androgen receptor (AR) and estrogen receptor (ER). The previously announced preliminary clinical trial results showed that ARV-471 had the potential to be a best-in-class estrogen receptor degrading agent. In the Phase 1/II clinical trial of ARV-110 in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), the prostate-specific antigen (PSA) level of 40% of patients with specific gene mutations reduced by more than 50%. The molecular structure and the process of drug discovery and optimization of those PROTACs have also attracted great attention.

Compared with the current drug development technologies, PROTAC technology (https://www.creative-biolabs.com/protac/protac-molecule-discovery.htm) does not require active sites, targets scaffold proteins, and can eliminate target proteins.

Proteolysis targeting chimera (PROTAC) is a technology based on the ubiquitin-proteolysis system to induce the degradation of target proteins through small molecule compounds.

Researchers from Proteinix Corporation filed a patent application in 1999 for using small molecule compounds to degrade specific proteins based on the ubiquitin mechanism. Two years later, Craig Crews from Yale University and Raymond Joseph Deshaies from Caltech reported in the PNAS paper in 2001 that peptide-based bifunctional small molecules induced the degradation of MetAP-2 protein, and formally proposed the concept of PROTAC. However, as it is difficult for peptide compounds to enter cells, the first generation of PROTAC failed.

Until 2008, the Crews team designed a second-generation PROTAC that can be used to degrade androgen receptor (AR) based on E3's ubiquitin protein ligase MDM2. In 2015, the Crews team designed a new generation of PROTAC that reduced the levels of multiple proteins by more than 90% based on the new E3 ubiquitin ligase VHL and CRBN ligands.

In the same year, James Bradner, head of Novartis' R&D department, published a new generation of PROTAC molecules based on thalidomide analogs in Science, which detonated the entire field. Professor Crews established Arvinas, the world's first drug research and development company using PROTAC technology in 2013, whose ARV-110 and ARV-471 have entered the second phase of clinical research.

So far, although the research on protein degrading agents mainly focuses on tumors, there have been breakthroughs in neurodegenerative diseases and inflammation/immunology. For example, IRAK4 is a non-cancer target that is related to arthritis, atherosclerosis, Alzheimer's disease, gout, systemic lupus erythematosus, psoriasis, etc. However, it was difficult to develop a drug against IRAK4 because of its scaffolding function that, even if inhibited, can still be bypassed to promote downstream inflammatory signal transduction.

Kymera believes that degradants can advance in a better manner than inhibitors. Sanofi cooperated with Kymera to develop KT-474, which is so far the only non-tumor PROTAC protein degradation drug (https://www.creative-biolabs.com/protac/) in the clinic, and suitable for atopic dermatitis and hidradenitis suppurativa.

The PROTAC based therapy has ushered in a new era with three PROTAC giants occupying many market shares, which are Arvinas, C4 Therapeutics, and Kymera Therapeutics, and many CROs exploring innovative methods for discovering new drugs against previously incurable diseases, such as Creative Biolabs.

In addition to PROTAC, progress has been made in the compound of molecular glue degradants that can also destroy E3 ligase without using long linkers and bulky target ligands.

The toolkit for developing PROTAC is also growing rapidly. Currently, many large pharmaceutical companies are investing in these small molecules, and academic institutions and start-up companies are also developing degradants that can be used in clinics. According to PROTAC-DB, an online database of PROTACs, there are now more than 1,600 publicly PROTAC degradants disclosed with more than 100 targets. Although there is no drug approved by the FDA so far, PROTAC will eventually usher in a prosperous era after more than 20 years of accumulation.

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