Ligand Design for Estrogen Receptor (ER)-targeting PROTAC^®

Serving as a leader and supplier in the biochemical market, Creative Biolabs is dedicated to offering a wide spectrum of ER-based ligand design services for the proteolysis targeting chimera (PROTAC^®) development. Our scientists specialized in molecule discovery studies will work with you to develop a most appropriate strategy that will offer the most meaningful data for your research. We have experienced experts and advanced platforms that can provide excellent services in this field.

Introduction to Estrogen Receptor (ER)

In the past few years, two subtypes of the estrogen receptor (ER), ERα and ERβ, have been identified in different mammalian species, such as humans and rats. ERs consist of several functional domains (A-F domain). In general, the A and B domains are responsible for regulating the ER-based transcription and activation. The C domain, also known as a DNA binding domain, is capable of binding to specific estrogen-responsive genes. The D domain is composed of the hinge region, activation function (AF)-2a and part of the ER nuclear signal region. The C-terminal of E and F domains contain the ligand-binding region, the protein binding region, as well as the AF-2 transactivation domain. Additionally, many studies have demonstrated that ER and its signaling pathway are associated with the development and progression of various human cancers, especially for breast cancer, ovarian cancer, and colon cancer. Moreover, PROTAC^® technology has been developed for inducing ER protein degradation by using the E3 ligase system. Recent researchers have revealed that PROTAC^®-based ER degraders should be a powerful tool for treating estrogen receptor-positive (ER+) human cancers.

Fig.1 A general scheme for the design of ER degraders based upon the PROTAC^® concept. (Hu, 2019)

Our Ligand Design Platform for ER-targeting PROTAC^®

PROTAC^® technology has been considered as an effective method for analyzing the functional role of target proteins. Molecules generated by PROTAC^® contain two main ligands, one is designed to bind to specific proteins, and another ligand is widely used for connecting cell E3 ubiquitin ligase system. Furthermore, these two ligands are usually joined by a chemical linker.

Recently, PROTAC^® technology has aroused much attention due to the availability of different ligands for nuclear receptors, such as ERs, and it has been employed for designing a wide variety of small-molecule degraders for proteins. As a consequence, Creative Biolabs offers a wide range of new ER ligand design services based on PROTAC^® technology. In our company, we have successfully established a comprehensive PROTAC^® ligand design platform to help your design, synthesis, and evaluation of novel ER ligands to treat different ER+ cancers. For instance, the E3 ligase recognition motif will be synthesized by using peptides synthetic strategy. The modified handle will be utilized to produce the chimeric molecules. PROTAC^®-induced degradation of the target protein will be further examined by the specific cell lines, and the expression of ER protein will be then detected in ER-targeting PROTAC^® therapy. Up to now, different kinds of ERs, such as small-molecule, peptide, and antibody, can be used to design new ligands for providing effective or improved treatment in cancers.

As a leading global CRO company, Creative Biolabs aims to help our worldwide customers shorten the discovery and development time in novel drugs. We are glad to offer ligand design and modification services for our clients. For more detailed information, please feel free to contact us or directly sent us an inquiry.

Reference

1. Hu, J.; et al. Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC^®) Degrader of Estrogen Receptor (ER). J Med Chem. 2019, 62(3): 1420-1442.