Ligand Design for Androgen Receptor (AR)-targeting PROTAC^®

Creative Biolabs, who has many years of experience in antibody development, has also conducted extensive and in-depth research on PROTAC^® technology to build a comprehensive PROTAC^® development service system.

Androgen Receptor (AR) and AR-related Disease

Androgen receptor (AR) belongs to the steroid receptor in the nuclear receptor superfamily. It is distributed and expressed in skeletal muscle, liver, fat, brain and other tissues. The main form of androgens is testosterone. In addition to reproduction, androgens also maintain hormone balance in the body, stimulate protein metabolism, promote nitrogen deposition, and increase the number and thickness of muscle fibers. AR's most important function is to regulate DNA expression as a DNA-binding transcription factor. Testosterone / AR can regulate almost all pathways related to glucose and lipid metabolism and obesity-related diseases, including key enzymes and proteins of glucose and lipid metabolism, nuclear transcription factors (PPARγ, LXRα, FoxO1), inflammatory response, leptin sensitivity of the hypothalamus, proliferation, and differentiation of adipocyte, mitochondrial function, and vascular endothelial cell function. More importantly, AR is also an important drug target for prostate cancer.

Structure of Androgen Receptor (AR)

There are currently two isoforms of AR, AR-A and AR-B. AR-B is a full-length form with a molecular weight of 110 kDa. However, AR-A lost the original 187 amino acid after being hydrolyzed by protease in vitro, is truncated at the N-terminus, and has a molecular weight of 87 kDa. Structurally, similar to other nuclear receptors, AR is modular and contains multiple functional domains from A to F (Fig.1). The N-terminal A / B is a regulatory domain, including: a) activation function 1 (AF-1) with amino acids 101-370, which is required for complete ligand activation activity; b) activation function 5 (AF-5) with amino acids 360-485, related to constant activity; c) dimerized surface with amino acids 1-36 (containing the FXXLF motif) and 370-494, both of which interact with the LBD head-to-tail within the molecule. C is the DNA binding region (DBD). D is the flexible hinge region connecting DBD and LBD. Together with DBD, it contains a ligand-related nuclear localization signal. E is the ligand binding region (LBD), which contains activation function 2 (AF-2) and ligand-dependent nuclear export signals. AF-2 is related to the activity induced by the agonist and can bind to the N-terminal FXXLF motif and co-activator proteins containing LXXLL or FXXFL. F is the C-terminal domain.

Fig.2 Structure of androgen receptor (AR).

Ligand Design for Androgen Receptor (AR)

AR ligands include agonist, mixed and antagonist types. Agonists include various endogenous androgens, such as testosterone, androstenedione, dihydrotestosterone, androstenediol, dehydroepiandrosterone, etc., and synthetic androgens such as methyltestosterone and oxandrolone. Mixed-acting ligands are primarily selective androgen receptor modulators such as andarine. Antagonists include steroids, nonsteroids, and N-terminal domain antiandrogens.

As an important target for prostate cancer and other diseases, the research on AR and its ligands is very extensive. Many of these antagonists are designed to target the ligand-binding region of the receptor. An important aspect of the development of PROTAC^® for AR is the design of suitable AR ligands. What is encouraging is that AR has been studied extensively, and the number of AR ligands that have been discovered is huge. As the research on the role of AR in the disease process and its structure continues, through the screening of existing compound libraries, new ligands may be further discovered. In addition, deep mining and optimization of existing AR ligands to meet the requirements of PROTAC^® therapy is also an efficient strategy.

Fig.3 Structure of nuclear receptor ligands.

Ligand Design Services

• Ligand discovery and identification
• Receptor-ligand conformational relationship and activity study
• Modification and optimization of existing ligands
• Ligand drugability and pharmacokinetics study
• Custom synthesis and manufacturing of ligands

Creative Biolabs offers different formats of AR ligand development services, including small molecules, peptides, proteins and antibodies. If additional help is needed, please directly contact us and consult our technical supports for more details.