SAT-341 Pharmacology and Metabolism of GLL398 an Oral Selective Estrogen Receptor Degrader for Endocrine Therapy of Breast Cancer

Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further demonstrates its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. Our laboratory has developed a boron-modified GW5638 analog, GLL398 that showed superior oral bioavailability while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604. Here we report further studies on the pharmacology, pharmacokinetics, and metabolism of GLL398. Given GLL398’s robust activities in breast cancer cells that are either tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), we first measured its binding behavior towards ER(Y537S). To better understand the mode of action we next performed molecular modeling of the binding of GLL398 and found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ER(Y537S). To test if the superior oral bioavailability can be translated to potent efficacy in vivo, mice bearing MCF-7 derived xenograft breast tumors and patient derived xenograft tumors harboring ER(Y537S) were treated with GLL398 which potently inhibited tumor growth in mice. Finally, the metabolism of GLL398 was also investigated to elucidate the biotransformation of the drug and its potential contribution to the superior oral bioavailability over GW7604.