In the autumn of 2013, Sanofi scientists Youssef El-Ahmad and his colleagues were working late at the company’s research center in Vitry, near Paris, France. They were trying to solve a problem that had been challenging them for years. It was not a new problem for these medicinal chemists, but they would eventually have to invent an entirely new chemical structure to solve it.
The job at hand was to break down a type of hormone receptor found on the surface of the most common and deadliest form of cancer affecting women today—breast cancer. Over 75% of breast cancers are classified as estrogen-receptor-alpha-positive (ER+), which means that the tumors use the cells’ receptors to capture and “feed” off of a woman’s own estrogen hormones to fuel their growth. Estrogen is the primary female sex hormone or signaling molecule that supports the development and regulation of the female reproductive system and other feminine characteristics. Breast cancer is categorized as a ‘hormone-based’ cancer because it uses estrogen to grow.
“When you are hunting for a treatment with a specific therapeutic activity, you need to also make sure that it has a chemical structure that can be processed easily by the body,” El-Ahmad explains. “Otherwise, you end up with a medicine that cannot fully reach its intended target and, therefore, cannot optimally do its job.”
A clear patient treatment need
For many decades, doctors have been able to treat breast cancer with hormone therapies that reduce or block the receptors’ ability to capture estrogen (used sometimes in combination with traditional chemotherapies). These so-called hormone modulators have yielded impressive results, keeping many cancers at bay or halting further growth in most cases.
But in about 30% of women with ER+ breast cancer, the tumor cells mutate the receptors over time, rendering this first line of treatment ineffective. Simply put, the mutation allows the receptors to trigger growth even in the absence of estrogen. “This is a mind-boggling adaptive response of these receptor proteins that is not yet fully understood,” adds Monsif Bouaboula, Associate Director of Cancer Cell Dependencies at Sanofi.
In 2002, the first in a new class of breast cancer treatments called selective estrogen receptor degraders (SERDs) became available to patients. Rather than merely blocking the receptors in the cancer cells, this new approach aims to degrade or break down these protein structures enough to stop them from fueling further cancer growth.
However, the therapeutic potential of the SERD approach in breast cancer treatment had yet to be fully realized, according to members of the healthcare community.
“Over the years, clinicians kept coming to us, voicing their frustrations that, not-withstanding currently available treatments, there remains a significant unmet treatment need in breast cancer care today. Specifically, they were asking for a SERD treatment that could be administered as an oral medication, easily processed in the body and, thus, have a chance of reaching the cancerous tissue in full dose to effectively degrade the targeted receptors.”
The right team to take on the challenge
Given the devastating nature of breast cancer and the apparent shortcomings of available treatments, Sanofi decided to pursue this in the hope of making the therapeutic promise of this class of treatments more accessible to women with ER+ breast cancers. The company’s expertise in the area of hormone receptor proteins and their strong track record of turning small molecules into medicines gave the team confidence they could be successful.
“We could take advantage of world-class expertise across our own R&D sites, specifically our chemistry teams in France and Germany and the pharmacology team in the US. We knew that we had the end-to-end skills needed to tackle this challenge,” recalls Bouaboula. The team started by defining the ideal characteristics they were looking for in a SERD candidate so they could search for a match, using robotics to scan hundreds of thousands of samples in the company’s chemical compound library. It took more than two years to find a candidate with a strong starting profile but, like current treatments, it still wasn’t easy to turn it into a medicine since it was not easily metabolized by the body.
This is where painstaking trial and error became essential. Step by step, the team of biologists and chemists worked in tandem to fine-tune the drug properties of the starting compound until it met every critical criterion they believed could lead to an optimal SERD candidate. Success was achieved when they invented a new compound that balanced metabolic stability and receptor binding potency sufficiently enough to warrant further exploration.
Theoretical depiction of how the selective estrogen receptor degrader or SERD compound works: Shown here in light blue, the investigational SERD compound binds selectively to sites on the receptor inside the tumor (shown mainly in dark blue) in order to cut off its estrogen-driven ‘food’ supply. The estrogen receptor (ER) is a protein which is found inside and outside of ER positive breast cancer cells that receives signals from the hormone that essentially tells the cancer to grow
In retrospect, El-Ahmad and his colleagues do not recall a specific “eureka moment” or even stopping to celebrate the discovery of a completely new SERD compound. “Yes, we were happy, but we quickly moved on to the next hurdle in front of us—preclinical and clinical testing.”
From in vitro to in vivo: clinical trials underway
Based on the anti-tumor activity the compound exhibited in preclinical breast cancer models, the company decided to move forward with human testing of this investigational compound, where it is currently in mid-stage clinical trials.
“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. For now, we can say we’ve built valuable expertise across the teams, optimizing a promising therapeutic approach to selectively degrade protein receptors on cancer cells that we believe could have application in other cancers as well,” Bouaboula asserts.
As for research team across Sanofi who contributed to discovering this new compound, they have already moved on, trying to solve the next challenge, but they continue to find inspiration in the experience. “It was 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 women with breast cancer,” says El-Ahmad.
The SERD candidate referenced in this article is an investigational compound which has not been evaluated for safety and efficacy in humans by any regulatory authority.
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b01293 • Publication Date (Web): 13 Nov 2019 https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.9b01293