Overcoming mutation-based resistance to antiandrogens with rational drug design
Abstract
The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 09, 2013
- Source ID
- 10.7554/elife.00499
Entities
People
- Charles Sawyers
- David J Hosfield
- Geoffrey L Greene
- John Wongvipat
- Michael J. Evans
- Minna D Balbas
- Philip A. Watson
- Vivek K. Arora
- Yang Shen
- Yu Chen
Organizations
- Congressionally Directed Medical Research Programs
- Geoffrey Beene Cancer Research Center
- Howard Hughes Medical Institute
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- National Institutes of Health
- Toyota Technological Institute
- Toyota Technological Institute at Chicago
- University of Chicago