A platform for research: civil engineering, architecture and urbanism
A platform for research: civil engineering, architecture and urbanism
De Novo Design of an Androgen Receptor DNA Binding Domain‐Targeted peptide PROTAC for Prostate Cancer Therapy
Androgen receptor splice variant‐7 (AR‐V7), one of the major driving factors, is the most attractive drug target in castration‐resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR‐V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR‐V7. Based on the homodimerization structure of the AR DBD, a novel peptide‐based proteolysis‐targeting chimera (PROTAC) drug is designed to induce AR and AR‐V7 degradation in a DBD and MDM2‐dependent manner, without showing any activity on other hormone receptors. To overcome the short half‐life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au)‐peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au‐AR pep‐PROTAC effectively degrades AR and AR‐V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC50 values 48.8 and 79.2 nM, respectively. Au‐AR pep‐PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au‐AR pep‐PROTAC can ultimately lead to a new therapy for AR‐V7‐positive CRPC.
De Novo Design of an Androgen Receptor DNA Binding Domain‐Targeted peptide PROTAC for Prostate Cancer Therapy
Androgen receptor splice variant‐7 (AR‐V7), one of the major driving factors, is the most attractive drug target in castration‐resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR‐V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR‐V7. Based on the homodimerization structure of the AR DBD, a novel peptide‐based proteolysis‐targeting chimera (PROTAC) drug is designed to induce AR and AR‐V7 degradation in a DBD and MDM2‐dependent manner, without showing any activity on other hormone receptors. To overcome the short half‐life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au)‐peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au‐AR pep‐PROTAC effectively degrades AR and AR‐V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC50 values 48.8 and 79.2 nM, respectively. Au‐AR pep‐PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au‐AR pep‐PROTAC can ultimately lead to a new therapy for AR‐V7‐positive CRPC.
De Novo Design of an Androgen Receptor DNA Binding Domain‐Targeted peptide PROTAC for Prostate Cancer Therapy
Ma, Bohan (author) / Fan, Yizeng (author) / Zhang, Dize (author) / Wei, Yi (author) / Jian, Yanlin (author) / Liu, Donghua (author) / Wang, Zixi (author) / Gao, Yang (author) / Ma, Jian (author) / Chen, Yule (author)
Advanced Science ; 9
2022-10-01
14 pages
Article (Journal)
Electronic Resource
English
Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy
| Wiley | 2024
Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy
| Wiley | 2024
Paired box2 upregulates androgen receptor gene expression in androgen-independent prostate cancer
| British Library Online Contents | 2014
Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy
| Wiley | 2022
UBX‐390: A Novel Androgen Receptor Degrader for Therapeutic Intervention in Prostate Cancer
| Wiley | 2024