LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy.

Autor:	Ning S; Department of Urologic Surgery, University of California Davis, Davis, California., Armstrong CM; Department of Urologic Surgery, University of California Davis, Davis, California., Xing E; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Leslie AR; Department of Urologic Surgery, University of California Davis, Davis, California., Gao RY; Division of Hematology and Oncology, University of California Davis, Davis, California., Sharifi M; Department of Urologic Surgery, University of California Davis, Davis, California., Schaaf ZA; Department of Urologic Surgery, University of California Davis, Davis, California., Lou W; Department of Urologic Surgery, University of California Davis, Davis, California., Han X; Department of Urologic Surgery, University of California Davis, Davis, California., Xu DH; Department of Urologic Surgery, University of California Davis, Davis, California., Yang R; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Cheng J; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Mohammed S; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Mitsiades N; Division of Hematology and Oncology, University of California Davis, Davis, California.; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California., Liu C; Department of Urologic Surgery, University of California Davis, Davis, California.; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California., Lombard AP; Department of Urologic Surgery, University of California Davis, Davis, California.; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California., Wu CY; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California., Cheng X; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Li PK; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio., Gao AC; Department of Urologic Surgery, University of California Davis, Davis, California.; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California.; VA Northern California Health Care System, Sacramento, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Nov 04; Vol. 84 (21), pp. 3617-3628.
DOI:	10.1158/0008-5472.CAN-24-0440
Abstrakt:	The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers, such as AR variants like AR-V7, and steroidogenic enzymes, such as aldo-keto reductase 1C3 (AKR1C3), to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here, we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and to inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide (Enza), abiraterone, apalutamide, and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to Enza treatment, and its combination with Enza further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR patient-derived xenograft models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer. Significance: LX1 simultaneously targets androgen receptor variants and the steroidogenic enzyme AKR1C3, offering a promising approach to combat drug resistance and enhancing therapeutic efficacy in conjunction with standard treatments for advanced prostate cancer. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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