More than 75 % of breast cancers are estrogen receptor alpha (ERa) positive and resistance to current hormone therapies occurs in one third of ER+ patients. Clinically resistant tumors are still ERa dependent, but mutations usually confer constitutive activation to the hormone-receptor, rendering ERa modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent Selective Estrogen Receptor Degrader (SERD), which degrades the ERa receptor in tamoxifen-resistant tumors which has been approved in 2002 for the treatment of hormone receptor positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties, linked to its low solubility, weak permeation and high metabolism which limit its efficacy in cancer patients.<br/>This lecture will describe the discovery of SAR439859, a novel, orally bioavailable SERD, which is a potent degrader of ERa both in vitro and in vivo. Elements of Structure-activity relationships of SAR439859 will be reported as well as preclinical and preliminary clinical data obtained in patient .<br/>SAR439859, is currently in phase I/IIa clinical development for the treatment of ERα positive breast cancer.

Discovery of SAR439859, an orally bioavailable Selective Estrogen Receptor Degrader (SERD) to treat ER+ breast cancers

2019 Fall National Meeting

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