Prostate cancer is one of the most common malignancies in men globally. Hormonal therapies targeting the androgen-androgen receptor (AR) axis have significantly delayed disease progression. However, drug resistance remains inevitable, and new therapeutic targets and strategies are required to overcome ARPI resistance.
In a study recently published in PNAS, a collaborative team led by Dr. LI Zhenfei from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, Dr. HU Youhong from the Shanghai Institute of Materia Medical of the Chinese Academy of Sciences, Dr. REN Ruobing from Fudan University and LIU Jia from the Shanghai Institute of Materia Medical of the Chinese Academy of Sciences leveraged AlphaFold2-predicted 3βHSD1 structure to design HEAL-116, a novel 3βHSD1 inhibitor with superior enzymatic activity and favorable pharmacokinetic properties, offering a new strategy for prostate cancer treatment and overcoming resistance to second-generation androgen receptor pathway inhibitors (ARPIs).
Previously, Dr. Li's team identified the metabolic enzyme 3βHSD1 as a key driver for prostate cancer progression. 3βHSD1 regulates the metabolism of androgen, progesterone, and abiraterone, mediating resistance to ARPIs. They also discovered biochanin A (BCA) as a potent 3βHSD1 inhibitor to suppress the development of prostate cancer in cell lines, mouse models, and even patients. However, BCA's low oral bioavailability hindered its clinical translation.
In this study, the collaborative team integrated AlphaFold2 protein structure prediction, molecular dynamics simulation, quantum chemistry calculation and other technologies to construct a high-precision structure model of 3βHSD1, revealing its unique catalytic mechanism and substrate-binding pocket characteristics.
Through systematic optimization of BCA's molecular geometry and charge distribution, the team developed HEAL-116, a highly specific inhibitor with enhanced binding affinity and improved oral bioavailability via hydrophilic group modifications. The in vivo and in vitro experiments showed that HEAL-116 potently suppressed 3βHSD1 activity and inhibited the growth of prostate cancer xenografts, when used alone or in combination with ARPIs. The specificity of HEAL-116 was also evaluated, showing no significant effects on transcriptome and kinome.
This study validated the AI-driven rational drug design strategy, providing a new approach to overcome prostate cancer drug resistance and advancing the clinical application of 3βHSD1-targeted therapy.
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