Artist's interpretation of proteasome

Targeting estrogen receptors in breast cancer

Article published November 25, 2019, updated November 2, 2020

Oncology researchers at Sanofi are investigating a compound that takes aim at ER+ breast cancer.

Around 75% of breast cancers are classified as "estrogen-receptor-positive" (ER+). In these cancers, the hormone estrogen sets off a series of events: 

  1. the estrogen diffuses across the cell membrane; 
  2. once inside the cell, it binds to an estrogen receptor; 
  3. two activated estrogen receptors combine to form a dimer; 
  4. the estrogen-receptor dimer enters the nucleus, where it…
  5. … helps switch on genes involved in tumor growth, replication, and development of tumor cells.

In their quest to foil tumors, Sanofi researchers are investigating a selective estrogen receptor degrader (SERD) – a type of molecule that, as the name implies, is designed to identify and destroy estrogen receptors.

The idea of targeting estrogen receptors is not new: for decades, doctors have treated some breast cancers with therapeutics that reduce or block the receptors’ ability to bind to estrogen. Often given in combination with chemotherapy, this approach keeps many cancers at bay for a time. 

But cancers are notorious evaders: in about 30–50% of people treated for ER+ breast cancer, tumor cells tinker with estrogen receptors, causing mutations that can interfere with treatments. 

Taking out cancer's enabler

“Over the years, clinicians kept coming to us, voicing their frustrations that there remains a significant treatment need in breast cancer care today. Specifically, they were asking for a SERD treatment that could be administered as an oral medication," said Youssef El-Ahmad, Group Leader, Medicinal Chemistry at Sanofi.

"Medicines taken orally can be metabolized fairly quickly. The challenge we have taken on is to design a molecule that, if taken in pill form, would potentially be stable enough to reach the tumor in sufficient dose before being metabolized, bind to estrogen receptors, and degrade them," explained Sanofi scientist Maysoun Shomali, biology project lead.

“When you are hunting for a treatment with a specific therapeutic activity, you need to make sure that it has a chemical structure that can be processed easily by the body. Otherwise, you end up with a medicine that cannot fully reach its intended target and, therefore, cannot optimally do its job,” added El-Ahmad.

SERD approaches estrogen receptor
SERD binds to estrogen receptor
SERD targets receptor for degradation

Caption: In this artist's interpretation, a SERD (1, blue) binds to the estrogen receptor where estrogen normally "docks" (2). Then, it targets the receptor for degradation (3). The clinical significance of these findings has not been established; Sanofi's investigational SERD has not been approved by any regulatory agency worldwide for the uses being researched.

Sanofi R&D chemistry and pharmacology teams in France, Germany, and the US tackled the challenge together. Their approach was to first define their ideal SERD candidate, then search for a match using robotics to scan hundreds of thousands of chemical compounds. Once they found a candidate, they fine-tuned its properties until it met all the team's criteria. 

The resulting investigational compound appeared to balance metabolic stability and receptor binding potency, and showed anti-tumor activity in breast-cancer models in the lab. All of this warranted further investigation in clinical trials. This research is ongoing – the molecule has not yet been evaluated for safety and efficacy in people by any regulatory authority. 

As this important project continues to progress through development, the scientists who joined forces to make it a reality look on their invention with pride. 

“One of the most rewarding things is knowing that some of the same clinicians who asked us to take on this challenge in the first place are now leading the clinical trials that will determine if this oral SERD compound will make it to patients," said Monsif Bouaboula, the global project leader and Group Head, Molecular Oncology at Sanofi. "A lasting benefit of this work is that we have built valuable expertise across the teams, optimizing a promising therapeutic approach to selectively degrade protein receptors on cancer cells.”

“It is a great human adventure to see the spirit of collaboration, the passion of so many researchers working together across geographies, each making their unique contributions critical to creating something new that has the potential to benefit people with breast cancer,” added El-Ahmad.

How protein degraders work

Source

  1. El-Ahmad Y, Tabart M, Halley F, et al. (2019). J Med Chem 63:512–528; https://doi.org/10.1021/acs.jmedchem.9b01293

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