Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 1

5492 - Basic selective estrogen receptor degraders (B-SERDs) in combination with novel BET inhibitors in ER+ breast cancer


28 Sep 2019


Poster Display session 1


Clinical Research

Tumour Site

Breast Cancer


Rui Xiong


Annals of Oncology (2019) 30 (suppl_5): v159-v193. 10.1093/annonc/mdz244


R. Xiong1, Y. Li2, J. Zhao1, F. Huang1, Z. Shen1, Y. Lu1, L. Gutgesell2, D.A. Tonetti1, G.R.J. Thatcher3

Author affiliations

  • 1 Pharmaceutical Sciences, University of Illinois at Chicago (UIC), 60612 - Chicago/US
  • 2 Pharmaceutical Sciences, University of Illinois at Chicago (UIC), 606127229 - Chicago/US
  • 3 Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago (UIC), IL 60612, - Chicago/US


Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 5492


Resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer drives mortality and despite new targeted therapies, resistance is the obstacle to progression-free survival. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) was approved in 2017 for fırst-line therapy of metaststic disease in postmenopausal women; however, acquired FUL-resistance in both fırst-line setting and in combination therapy with CDK4/6 inhibitor, palbociclib, has been observed clinically. The poor pharmacokinetics of FUL may contribute to acquired resistance.


Using structure-based design, we optimized: 1) novel SERDs bearing a basic side chain (B-SERDs) as an orally bioavailable and brain penetrant alternative to FUL; 2) novel pyridinone-based bromodomains and extra-terminal motif (BET) inhibitors to be used in combination with B-SERDs or FUL. Biochemical assays and growth inhibition of breast cancer cell lines, resistant to tamoxifen, and/or FUL, both in 2D and 3D cultures were used to optimize and select development candidates. Drug metabolism and pharmacokinetics(DMPK) demonstrated oral bioavailability and dose selection for validation in mouse xenograft models of endocrine resistant breast cancer.


B-SERDs showed equivalence to FUL in cell culture models, with respect to ERα degradation and antiproliferative activity; and in contrast to FUL, were demonstrated to have good oral and brain bioavailability. A development candidate with improved DMPK characteristics was effective in endocrine-resistant ER+ xenograft models. Novel BET inhibitors, optimized for potency in binding to BRD4-BD1 and selectivity over the larger family of bromodomain containing proteins, inhibited growth of tamoxifen and FUL-resistant breast cancer cells.Optimized compounds showed superior in vitro activity to eight BET inhibitors in clinical trials. The optimized BET inhibitor was validated alone and in combination with B-SERD in endocrine-resistant xenograft models.


The combination of B-SERD with BET inhibitor provides a multi-targeted suppression of ER signaling that may extend progression-free survival and cdircumvent acquired resistance in metastatic ER+ breast cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Gregory R J Thatcher.


Has not received any funding.


All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.