SC912 inhibits AR-V7 activity in castration-resistant prostate cancer by targeting the androgen receptor N-terminal domain.

Autor: Yi Q; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Han X; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada., Yu HG; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Chen HY; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Qiu D; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada., Su J; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada., Lin R; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Batist G; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Wu JH; Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, 3755 Cote-Ste-Catherine, Rd, Montreal, QC, H3T 1E2, Canada. jian.h.wu@mcgill.ca.; Departments of Oncology and Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada. jian.h.wu@mcgill.ca.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 May; Vol. 43 (20), pp. 1522-1533. Date of Electronic Publication: 2024 Mar 26.
DOI: 10.1038/s41388-024-02944-2
Abstrakt: Androgen deprivation therapies (ADT) are the mainstay treatments for castration-resistant prostate cancer (CRPC). ADT suppresses the androgen receptor (AR) signaling by blocking androgen biosynthesis or inhibiting AR with antiandrogens that target AR's ligand-binding domain (LBD). However, the ADT's effect is short-lived, as the AR signaling inevitably arises again, which is frequently coupled with AR-V7 overexpression. AR-V7 is a truncated form of AR that lacks the LBD, thus being constitutively active in the absence of androgens and irresponsive to AR-LBD-targeting inhibitors. Though compelling evidence has tied AR-V7 to drug resistance in CRPC, pharmacological inhibition of AR-V7 is still an unmet need. Here, we discovered a small molecule, SC912, which binds to full-length AR as well as AR-V7 through AR N-terminal domain (AR-NTD). This pan-AR targeting relies on the amino acids 507-531 in the AR-NTD. SC912 also disrupted AR-V7 transcriptional activity, impaired AR-V7 nuclear localization and DNA binding. In the AR-V7 positive CRPC cells, SC912 suppressed proliferation, induced cell-cycle arrest, and apoptosis. In the AR-V7 expressing CRPC xenografts, SC912 attenuated tumor growth and antagonized intratumoral AR signaling. Together, these results suggested the therapeutic potential of SC912 for CRPC.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: