Selective estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs): a patent review (2015-present)

ABSTRACT

Introduction

The estrogen receptor (ER) is a clinically validated oncology target with a pivotal role in hormonally driven breast cancer, the most prevalent form of female cancer. Current treatments that directly modulate ER include antagonists (SERMs), such as tamoxifen, and degraders (SERDs), such as fulvestrant which is administered by intramuscular injection.

Areas covered

This review covers patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) between the period January 2015 to June 2021. A total of 114 patent applications from 23 different applicants are evaluated with stratification into acidic SERDs, basic SERDs, and SERCAs.

Expert opinion

The clinical success of fulvestrant in the treatment of ER⁺ breast cancer has spurred research over the last decade into the discovery and development of novel SERDs, with a particular focus on the discovery of orally bioavailable drugs. This has resulted in a diverse range of candidates entering clinical trials. Although some have faltered in development, a cohort of oral SERDs has generated encouraging efficacy and safety data that has allowed advancement into late stage clinical trials. Data from these trials is eagerly awaited, with these molecules having the potential to offer significant benefits in the treatment of ER⁺ breast cancer.

KEYWORDS:

• Estrogen receptor
• SERD
• SERCA
• degrader
• covalent antagonist
• breast cancer

Funding

This paper was not funded.

Article highlights

• Breast cancer is the most prevalent cancer in women and can also develop in men. Around 70% of breast cancers express ER and anti-hormonal interventions using aromatase inhibitors, such as anastrozole, or SERMs, such as tamoxifen, have been the mainstay of treatment for the disease.

• The only clinically approved SERD, which has the ability to fully antagonize and also effect degradation of ER, is fulvestrant. The clinically approved dose of 500 mg is administered by intramuscular injection potentially limiting the clinical efficacy achievable. This has driven research into orally bioavailable SERDs, which offer the potential of improved efficacy.

• Patent applications describing SERDs and SERCAs from January 2015 to June 2021 are collated and analyzed in this article. The material covers 114 applications from 23 different applicants and builds on decades of prior research and investigation into the estrogen receptor.

• The work described in the patent applications analyzed below has led to a number of candidates entering the clinic. At the time of writing, more than 8 remain in active development with the most advanced in phase III pivotal studies and with the potential to bring significant benefit to patients with breast cancer.

Declaration of interests

The authors are employees and shareholders of AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.