ERα-Targeting PROTACs Show Preclinical Promise Against ER+ Breast Cancer

Share this content:
An orally-available formulation of proteolysis-targeting chimera successfully degraded and reduced levels of estrogen-receptor alpha protein.
An orally-available formulation of proteolysis-targeting chimera successfully degraded and reduced levels of estrogen-receptor alpha protein.

In preclinical cell-line and xenograft models, an orally-available formulation of proteolysis-targeting chimera (PROTAC) successfully degraded and reduced levels of estrogen-receptor alpha (ERα) protein—a driver in estrogen receptor-positive (ER+) breast cancer, according to findings presented at the 2016 San Antonio Breast Cancer Symposium. 1

“PROTAC-mediated degradation provides a distinct mechanism for reducing ERα, distinct from fulvestrant or currently available clinical selective estrogen-receptor degraders (SERDs),” reported John J. Flanagan, PhD, of Arvinas LLC, New Haven, Connecticut. “Oral administration of PROTACs reduced ERα levels in ER+ cell xenografts and in rat uteri.”

PROTACs are small-molecule drugs that degrade rather than inhibit target proteins by recruiting an existing cellular quality-control mechanism: the E3 ubiquitin ligase system. A ERα ligand is attached to an E3 ligase recognition domain, and these PROTAC payloads then attach to encountered ERα molecules and E3 ligase molecules, tagging the resulting package for degradation via the proteome, Dr Flanagan explained. Theoretically, the released PROTAC should then be able to repeat the process.

The ERα-targeting PROTAC offered “robust and selective” ERα degradation in breast cancer cells lines, and ERα degradation and tumor growth inhibition in MCF7 cell-derived xenograft mouse and rat models, Dr Flanagan said.

RELATED: Exercise and Gene Expression in Breast Cancer

Oral PROTACTs are undergoing preclinical testing “in a variety of clinically-relevant models,” Dr Flanagan said.

The PROTAC paradigm of drug design might allow the targeting of both druggable and “undruggable” components of the proteome, according to the Arvinas LLC website. PROTACs are also under development for use against prostate cancer.

Reference

  1. Flanagan JJ, Rossi AK, Anderoli M, et al. Targeted and selective degradation of estrogen receptor (ER) alpha by PROTACs. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.

Related Resources

You must be a registered member of Cancer Therapy Advisor to post a comment.

Sign Up for Free e-newsletters

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Prostate Cancer Regimens Drugs
Rare Cancers Regimens
Renal Cell Carcinoma Regimens Drugs
Skin Cancer Regimens Drugs
Urologic Cancers Regimens Drugs