In recent years, the biopharmaceutical market has shown a trend of rapid growth, in which the research and development of innovative drugs has become the focus of attention. As an innovative drug development model, target protein degradation technology has achieved remarkable results in preclinical research. Here, the author combines market trends, research and development progress and other factors to predict the PROTAC drugs that are expected to be approved in 2025, and looks forward to the future development prospects of this technology.

Three drugs are making rapid progress
Up to now, protein degraders have made significant progress in clinical research. According to incomplete statistics, a total of 36 protein degradation agents have entered the clinical stage around the world, and the total number of protein degradation R&D pipeline projects worldwide has exceeded a thousand. Among the 10 PROTACs that are expected to be approved, the indications are concentrated in cancer, accounting for about 80% , only 20% of drug indications are for other diseases such as autoimmune diseases, androgenetic alopecia. Among these compounds, three drugs are in clinical phase II or above, namely ARV-471 developed by Arvinas and Pfizer, KT-474 developed by Kymera Therapeutics and Sanofi, and GT20029 developed by Kintor Pharmaceuticals.

ARV-471 is a PROTAC drug developed by Arvinas, which has been jointly developed by Arvinas and Pfizer to commercialize the product since 2021. ARV-471 is a CRBN-based estrogen receptor PROTAC degrader indicated for the oral treatment of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) locally advanced or Patients with metastatic breast cancer. The product is currently in Phase III clinical research, and the FDA has granted Fast Track designation to study ARV-471 monotherapy in adult patients with ER+/HER2- locally advanced or metastatic breast cancer.

KT-474 (SAR444656) is a potential "first-in-class" IRAK4 degrader that is being developed for the treatment of immune-inflammatory diseases with significant patient needs such as hidradenitis suppurativa and atopic dermatitis, as well as other potential disease. Currently, KT-474 has completed Phase 1 clinical trials. Sanofi and Kymera reached a research and development cooperation worth up to US$2 billion in 2020 to jointly develop potential "first-in-class" protein degradation therapies targeting IRAK4 to treat immune-inflammatory diseases. In July 2024, Kymera said that Sanofi plans to expand its ongoing Phase II clinical trials in hidradenitis suppurativa (HS) and atopic dermatitis (AD) to advance this innovative therapy to the critical stage more quickly. sexual clinical research phase.

GT20029 is an androgen receptor (AR)-targeted degradation agent independently developed by Suzhou Kaoru Pharmaceutical. It is used to treat androgenic alopecia and acne. It treats hair loss caused by excess androgen by degrading the androgen receptor protein. problem. GT20029 is also the first topical PROTAC compound to enter clinical practice. It is used to treat androgenic alopecia and acne. On April 21, 2024, Kintor Pharmaceutical announced that the China Phase II clinical trial of GT20029 tincture for topical treatment of male androgenic alopecia has reached the primary research endpoint. Currently, Kintor Pharmaceuticals is actively deploying follow-up clinical strategies for GT20029.

Moving towards new target areas
The initial development of target protein degradation technology mainly focused on commonly used drug targets, such as ER, AR and BTK. However, the development focus of new generation TPDs has shifted to more innovative targets, with 70% of preclinical projects aimed at targeting traditionally “undruggable” proteins, including the transcription factors GTPases and guanosine exchange factors (GEFs). etc., targeted protein degradation technology has greatly expanded the range of druggable targets, making previously inaccessible targets feasible.

Among them, Kymera Therapeutics has a positive attitude in PROTAC research. The first clinical project targets IRAK4, and its protein degrader KT-474 is in Phase IIb trials. It is the first heterobifunctional protein degrader to enter clinical development and has achieved remarkable results in exploring the relationship between the structure and function of the IRAK4 protein.

In addition, according to phase I clinical trial data released in June this year, the potential "first-in-class" STAT3 targeted degrader KT-333 developed by Kymera Therapeutics has shown anti-tumor activity in a variety of hematological malignancies. KT- 333 is expected to become the first degrader targeting undrugged transcription factors to enter the clinic. Its next clinical drug candidate, KT-621, targets STAT6 and is currently in the development stage for the treatment of atopic dermatitis, asthma, and chronic obstructive pulmonary disease. On October 9, 2024, Kymera officially announced that its clinical trial application for KT-621 new drug has been approved by the FD. KT-621 may be the first oral immunology drug that does not require compromise in efficacy.

It is worth mentioning that Arvinas and BMS also have plans for "hard-to-drug targets." ARV-393 developed by Arvinas is a PROTAC drug targeting the BCL6 protein and is currently undergoing Phase I clinical research. Preliminary studies have shown that ARV-393 shows a deep BCL6 degradation effect in vivo and in vitro, and exhibits excellent tumor growth inhibition (TGI) effects in a variety of tumor xenograft models; BMS-986458 is a drug developed by BMS BCL6 degrader. The drug is currently in clinical phase I for the treatment of non-Hodgkin's lymphoma, and relevant data has not yet been disclosed.

Four major innovation directions
Protein degraders have made some progress in entering the field of new targets, but they also face many limitations. Next-generation degrader technologies have the potential to overcome these limitations through innovative improvements in ligands, pathways, delivery, and activation.

Ligand Innovation: New ligands for E3 ligases and proteins of interest (POIs) provide avenues to expand new targets and improve tissue specificity, thereby improving disease applicability and safety. Although there are over 600 E3 ligases in humans, the ubiquitously expressed CRBN is recruited by almost all current degraders. Expanding the types of E3 ligases recruited can increase targeting to cancer cells and reduce the impact on tissues. Additionally, POI ligands can be expanded to more “undruggable” targets; for example, RNA-PROTAC uses short oligonucleotides to degrade ribonucleoproteins.

Pathway innovation: extracellular proteins (MoDE) and lysosome targeting chimeras (LYTAC) extend the range of degradable target proteins outside the cell. Autophagy-targeting chimeras (AUTACs) use the autophagy-lysosomal pathway to provide E3 ligase-independent access to intracellular proteins and organelles.

Delivery Innovation: Targeted protein degradation technologies can leverage advances in antibody conjugates (DACs), nanotechnology (Nano-PROTACs), and click chemistry (CLIPTACs) to increase specificity and potency. dac can recognize receptors expressed on target cells, and Nano-PROTACs can respond specifically to tumors and achieve precise delivery to cancer cells. Cliptac is delivered in two smaller self-assembling tablets, which improves oral bioavailability.

Activation innovation: Targeted activation can achieve drug degradation in specific space or time, such as light conditions (PHOTAC), low oxygen conditions (hypoxia-activated PROTAC) or additional POI conditions (trivalent PROTAC). However, these methods face limitations in specificity and oral bioavailability.

Looking to the future, although the field of target protein degradation is still facing the challenge of insufficient clinical data, companies are expected to use a variety of strategies, including precise screening of degradation targets, innovative development of ligands, and the use of advanced computational methods for degradation design and optimization. Gradually address this issue.

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