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Discovery of the improved antagonistic prolactin variants by library screening
Yun Liu1, Wei Gong, Jens Breinholt
1Novo Nordisk China R&D, 29 Life Science Park Road, Beijing, China. yunl@novonordisk.com
Abstract:
Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.
Insights
Researchers developed a new variant of prolactin (PRL) with significantly increased affinity for its receptor. This breakthrough could lead to more effective treatments for hormone-related cancers like breast and prostate cancer.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Prolactin (PRL) stimulates mammary epithelium growth and is implicated in breast and prostate cancer.
- Existing prolactin receptor (PRLR) antagonists lack sufficient in vivo potency due to low receptor affinity.
Purpose of the Study:
- To develop novel PRLR antagonists with higher receptor affinity for improved therapeutic potential.
- To identify specific mutations in human G129R-PRL that enhance binding to the PRLR.
Main Methods:
- Generation of Site 1 focused protein libraries of human G129R-PRL mutants.
- Screening of mutant libraries for enhanced affinity to the human PRLR.
- Characterization of a novel G129R-PRL variant with combined mutations.
Main Results:
- Identified a novel G129R-PRL variant with mutations at Site 1.
- This variant exhibits a nearly 50-fold increase in antagonistic potency in vitro.
- The enhanced affinity addresses the limitations of previous PRLR antagonists.
Conclusions:
- The novel G129R-PRL variant demonstrates significantly improved PRLR antagonistic properties.
- This finding is crucial for developing more effective treatments for PRL-dependent cancers.
- Higher receptor affinity is key to advancing PRLR-targeted therapies.
