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.
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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.
- 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.