Regina Kelder

Oral Candidate Drug That Destroys Estrogen Receptors Looks Promising

How collaboration helped discover a novel and potent breast cancer compound out of 3,999 others

Of the estimated 2.3 million women diagnosed with breast cancer last year, around 75% are

Simon Goodacre, Charles River Scientist
Simon Goodacre, PhD

classified as estrogen-receptor positive, meaning that the tumor cells grow in response to estrogen; about 65% of these also grow in response to progesterone.

There is already an array of medications on the market to treat women with ER+ tumors. For decades, doctors have used a combination of therapeutics to block a receptor’s ability to bind to estrogen, often given in combination with chemotherapy.

But for 30-50% of people treated for ER+ breast cancer, the tumors fiddle with the estrogen receptors, causing mutations that can interfere with treatments. To overcome this obstacle, scientists developed selective estrogen receptor degraders (SERDs), administered intramuscularly, that are designed to target and destroy estrogen receptors. While effective in patients with metastatic breast cancer, the route of administration and low bioavailability are limitations.

Fabien Roussel, Charles River Scientist
Fabien Roussel, PhD

So, scientists have been endeavoring to develop an oral SERD as an alternative. One of those oral SERDs, developed by Genentech, was among the first to be tested in patients and is currently being tested in multiple clinical trials, including a Phase III trial for locally advanced or metastatic breast cancer treatment. Findings about the discovery of GDC-9545 (Giredestrant) recently appeared in the Journal of Medicinal Chemistry Among the study’s many authors were several Charles River scientists who conducted work on GDC-9545 as part of an integrated drug discovery project with Genentech.

Eureka caught up with two of the study’s co-authors from Charles River – Simon Goodacre, PhD, Project Manager, Business Optimisation and Fabien Roussel, PhD, Research Leader. Both are part of Charles River’s UK Discovery Team.

This is part of our ongoing series, Research Notes, where our blog highlights the recently published work of our scientists.

What was the purpose of this breast cancer study?

To design and synthesise an orally bioavailable, potent, and selective estrogen receptor antagonist and degrader to treat ER+ breast cancer—a critical unmet medical need and a global healthcare priority.

How did Charles River contribute to this study?

Our CRL team was part of a Genentech-led, fully integrated, global drug discovery project where teams from Genentech, CRL and a third party CRO worked together to deliver a clinical candidate. The CRL medicinal chemistry team utilised property and structure-based drug design to select new targets, balancing potency, degradation of the receptor, selectivity, and bioavailability. Our highly skilled synthesis team at CRL designed routes to challenging chiral molecules and used complex chemistry to successfully complete the synthesis. The CRL biology team worked closely with their key counterparts at Genentech to select and develop a complex but robust assay cascade that allowed the project to assess the synthesised molecules and to select the development candidate.

What were the findings and why are they significant in the future of this drug and breast cancer research?

The CRL team successfully contributed to the discovery of an oral selective estrogen receptor degrader (SERD), named GDC-9545 or Giredestrant, which displays an overall profile superior to known SERDs and SERMs. After profiling over 4,000 compounds encompassing multiple scaffolds with different mechanisms of action, Giredestrant emerged as our top lead with an overall best profile, including antagonist, degradation, and antiproliferation potency, DMPK properties, and in vivo efficacy and safety. In addition to robust single agent activity in xenograft models, Giredestrant in combination with other targeted therapies such as CDK4/6 inhibitors, was well-tolerated and resulted in greater efficacy than each agent alone without any drug−drug interaction liability. Giredestrant is currently being tested in multiple clinical trials including a Phase III trial for locally advanced or metastatic breast cancer treatment. The development of this molecule is an important milestone in the development of new drugs to treat the millions of people worldwide that develop breast cancer each year.