# Development of a Precision Drug to target Y537S Mutant Estrogen Receptor in Metastatic Breast Cancer

> **NIH NIH R03** · BAYLOR COLLEGE OF MEDICINE · 2022 · $80,000

## Abstract

ABSTRACT
Breast cancer is the most frequently diagnosed cancer and the second leading cause of death in American
women. The majority of breast cancer (~75%) expresses estrogen receptor α (ERα) protein and therefore
inhibition of this protein function by endocrine therapy is the mainstay of treatment in ER-positive breast cancer
patients. Nevertheless, acquired resistance has developed in nearly half of women treated with endocrine
therapy that is associated with poor patient survival. Specifically, in a substantial number of cases, prolonged
treatment with endocrine therapy creates the development of resistant tumor cells and, consequently, tumor
relapse, which manifests as metastatic disease that is extremely difficult to manage. Recently, deep DNA
sequencing has identified somatic mutations at specific sites in the ERα gene (ESR1) in a large subset of patients
with breast cancers that have spread. Specifically, Y537S and D538G mutations make ERα resistant to current
endocrine therapy and therefore, it is important to develop a novel targeted therapy to address these clinical
challenges by inhibiting ERα mutant proteins using next-generation ERα antagonist. Our long-term goal is to
develop more effective and safer small molecule drugs that block constitutively active mutant ER for treating
endocrine resistant metastatic breast cancer and have the potential to significantly improve current therapeutic
targeting strategies. The short-term goal of this R21 application is to identify and develop specific drug-like
probes and nominate preclinical candidates to target ER mutant protein by using a DNA-encoded chemical
library (DEL) screening platform. The objective of this proposal will be evaluated by addressing the following
specific aims: 1. We will perform DNA-encoded chemical libraries screen to identity small-molecule binders to
the ligand-binding domain of mutant ERα protein. 2. We will validate and prioritize lead compounds by using
biochemical and functional studies. Our central hypothesis is that small molecule antiestrogens with high affinity
and specificity for ERα mutants can inhibit ERα mutant function in breast cancer. This research will lay the
groundwork for more detailed follow up studies for future applications. After successful execution of this proposed
research plan, we expect to have identified lead compounds for mutant ER and that can be used for future pre-
clinical and clinical studies.

## Key facts

- **NIH application ID:** 10359449
- **Project number:** 1R03CA259664-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Murugesan Palaniappan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $80,000
- **Award type:** 1
- **Project period:** 2021-12-13 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359449

## Citation

> US National Institutes of Health, RePORTER application 10359449, Development of a Precision Drug to target Y537S Mutant Estrogen Receptor in Metastatic Breast Cancer (1R03CA259664-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359449. Licensed CC0.

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