# Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor

> **NIH NIH R35** · DARTMOUTH COLLEGE · 2022 · $409,560

## Abstract

Project Summary /Abstract
Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under
physiological conditions, represent ~40% of the human proteome, have crucial functional roles in a variety
of biological pathways and biomolecular assemblies and are implicated in a large number of human
diseases. As IDPs populate a dynamic conformational ensemble of rapidly interconverting structures in
solution, and cannot be represented by a single dominant conformation, or even a small number of
substantially populated conformations, they are not suitable targets for conventional structure-based drug
design methods. If it becomes possible to target IDPs with small molecule drugs, the druggable proteome
will be dramatically expanded and therapeutic interventions may become accessible for currently
untreatable diseases
The PI’s laboratory utilizes an integrated computational and experimental research strategy to combine
state-of-the-art all-atom molecular simulations with experimental measurements from NMR spectroscopy
and other biophysical experiments to obtain atomistic descriptions of the dynamic binding mechanisms of
IDPs and uses insights form these binding mechanisms to predict and rationally design novel binding
interactions. This proposal focuses on applying this integrated computational and experimental approach
to elucidate the binding mechanisms of small molecule drug candidates that target that intrinsically
disordered domain of the androgen receptor and have entered clinical trials for castration resistant prostate
cancer (CRPC). These binding mechanisms will be used to inform the rational design more potent and
selective androgen receptor inhibitors and more effective CRPC therapeutics
. This proposal describes a
remarkable opportunity to draw connections between molecular binding mechanisms studied by molecular
simulations and NMR, biological activity observed in cellular assays, and clinical results from human
CRPC drug trials.
This proposal will initiate a sustainable long-term research effort to combine computational and
experimental methods to study the dynamic interactions of IDPs in a variety of cellular and pharmaceutical
contexts. This research effort will stimulate the development of robust platforms to integrate computational
and experimental methods that will dramatically increase the number of proteins amenable to structural and
mechanistic characterization and pharmaceutical targeting and will provide new avenues to therapeutic
interventions in diseases associated with aberrant biological interactions of IDPs such as those mediated by
biomolecular condensate formation and protein misfolding.

## Key facts

- **NIH application ID:** 10486084
- **Project number:** 5R35GM142750-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Paul Robustelli
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,560
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486084

## Citation

> US National Institutes of Health, RePORTER application 10486084, Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor (5R35GM142750-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10486084. Licensed CC0.

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