Invented by Andrew J. Phillips, Christopher G. Nasveschuk, James A. Henderson, Minsheng He, Kiel Lazarski, C4 Therapeutics Inc

The market for degraders and degrons to target protein degradation has been rapidly growing in recent years. Protein degradation is a crucial process in maintaining cellular homeostasis, as it allows for the removal of unwanted or damaged proteins. Dysregulation of protein degradation has been linked to various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases. Therefore, the development of degraders and degrons has become an area of intense research and commercial interest. Degraders are small molecules or biologics that can selectively bind to target proteins and recruit them to the cellular degradation machinery. They work by hijacking the ubiquitin-proteasome system, which is responsible for the degradation of most cellular proteins. By tagging the target protein with ubiquitin, degraders facilitate its recognition and subsequent degradation by the proteasome. This targeted protein degradation approach offers several advantages over traditional inhibition strategies, as it allows for the complete removal of the target protein rather than just inhibiting its activity. Degraders can be classified into two main categories: PROTACs (PROteolysis TArgeting Chimeras) and molecular glues. PROTACs are bifunctional molecules that consist of a ligand for the target protein, a ligand for an E3 ubiquitin ligase, and a linker connecting the two. When a PROTAC binds to the target protein, it brings it in close proximity to the E3 ligase, leading to its ubiquitination and subsequent degradation. Molecular glues, on the other hand, work by promoting the interaction between the target protein and an E3 ligase, without the need for a linker. Degraders have shown promising results in preclinical and early clinical studies, with several candidates currently in development. One of the most notable success stories in this field is the development of degraders targeting the protein BRD4, which is involved in various cancers. These degraders have demonstrated potent anti-cancer activity and are currently being evaluated in clinical trials. Additionally, degraders targeting other proteins, such as BTK (Bruton’s tyrosine kinase) and BET (bromodomain and extra-terminal domain), have also shown promising results in preclinical studies. The market for degraders and degrons is expected to grow significantly in the coming years, driven by the increasing understanding of protein degradation pathways and the potential therapeutic applications of targeted protein degradation. Several pharmaceutical and biotechnology companies have already entered this space, either through in-house research or collaborations with academic institutions and smaller biotech companies. Moreover, the market is also attracting the interest of investors, with significant funding being allocated to companies developing degraders and degron-based therapies. However, challenges still remain in the development of degraders and degrons. One major hurdle is the identification of suitable E3 ligases for specific target proteins, as not all proteins have well-characterized E3 ligases. Additionally, the design and optimization of degraders require a deep understanding of the target protein’s structure and function, as well as the interaction between the ligand and the E3 ligase. Nevertheless, advancements in protein engineering, computational modeling, and high-throughput screening techniques are helping to overcome these challenges and accelerate the development of degraders and degrons. In conclusion, the market for degraders and degrons to target protein degradation is rapidly expanding, driven by the potential therapeutic applications of targeted protein degradation in various diseases. The development of degraders and degrons offers a promising approach to selectively remove disease-causing proteins, providing new opportunities for drug discovery and development. With ongoing research and investment in this field, we can expect to see significant advancements in the coming years, potentially leading to the approval of the first degrader-based therapies.

The C4 Therapeutics Inc invention works as follows

Herein, “Pharmaceutical degraders and degrons for therapeutic applications” are described.

Background for Degraders and degrons to target protein degradation

I. Definitions

II. “II.


IV. Linkers

V. Linker-Degron Intermediates

VI. Target Proteins


A1 is S

and A1 = C?

and A1 = C?


IX. Combination Therapy

X. “X.

XI. “XI.


Example 1: Synthesis of Methyl 1-(2,4-Dioxo-3-azabicyclo[3.1.1]heptan-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Step 1: Preparation of Methyl 3-Cyano-3-((4-methoxybenzyl)amino)cyclobutane-1-carboxylate

Step 2: Preparation of 1-((4-Methoxybenzyl)amino)-3-azabicyclo[3.1.1]heptane-2,4-dione

Step 3: Preparation of 1-Amino-3-azabicyclo[3.1.1]heptane-2,4-dione

Step 4: Preparation of Methyl 1-(2,4-Dioxo-3-azabicyclo[3.1.1]heptan-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate

Example 2: Synthesis of 1-(4-Hydroxy-6-methyl-2-oxopyridin-1 (2H)-yl)-3-azabicyclo[3.1.1]heptane-2,4-dione

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