Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer. 2019

Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang

We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008297 Male Males
D011471 Prostatic Neoplasms Tumors or cancer of the PROSTATE. Cancer of Prostate,Prostate Cancer,Cancer of the Prostate,Neoplasms, Prostate,Neoplasms, Prostatic,Prostate Neoplasms,Prostatic Cancer,Cancer, Prostate,Cancer, Prostatic,Cancers, Prostate,Cancers, Prostatic,Neoplasm, Prostate,Neoplasm, Prostatic,Prostate Cancers,Prostate Neoplasm,Prostatic Cancers,Prostatic Neoplasm
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D011944 Receptors, Androgen Proteins, generally found in the CYTOPLASM, that specifically bind ANDROGENS and mediate their cellular actions. The complex of the androgen and receptor migrates to the CELL NUCLEUS where it induces transcription of specific segments of DNA. Androgen Receptors,5 alpha-Dihydrotestosterone Receptor,Androgen Receptor,Dihydrotestosterone Receptors,Receptor, Testosterone,Receptors, Androgens,Receptors, Dihydrotestosterone,Receptors, Stanolone,Stanolone Receptor,Testosterone Receptor,5 alpha Dihydrotestosterone Receptor,Androgens Receptors,Receptor, 5 alpha-Dihydrotestosterone,Receptor, Androgen,Receptor, Stanolone,Stanolone Receptors,alpha-Dihydrotestosterone Receptor, 5
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014183 Transplantation, Heterologous Transplantation between animals of different species. Xenotransplantation,Heterograft Transplantation,Heterografting,Heterologous Transplantation,Xenograft Transplantation,Xenografting,Transplantation, Heterograft,Transplantation, Xenograft

Related Publications

Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
February 2019, Journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
September 2022, European journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
October 2020, Acta pharmaceutica Sinica. B,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
October 2021, Bioorganic chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
January 2022, European journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
October 2020, Journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
March 2020, European journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
December 2021, European journal of medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
December 2023, Journal of enzyme inhibition and medicinal chemistry,
Xin Han, and Chao Wang, and Chong Qin, and Weiguo Xiang, and Ester Fernandez-Salas, and Chao-Yie Yang, and Mi Wang, and Lijie Zhao, and Tianfeng Xu, and Krishnapriya Chinnaswamy, and James Delproposto, and Jeanne Stuckey, and Shaomeng Wang
January 2023, Journal of medicinal chemistry,
Copied contents to your clipboard!