Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists

Abstract

Herein, we report the optimization of a metasubstituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Targeting the Estrogen Receptor for the Treatment of Breast Cancer: Recent Advances and Challenges

“…Recently, Scott et al reported a series of zwitterion-containing SERD antagonists for the treatment of ER+ BC . Among them, compound 18 was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines (Figure ).…”

“…Due to the presence of an acid moiety, compound 18 also has a very low PPB, which resulted in a high fraction unbound in PPB assays across species (>10% free). The CYP450 profile of this compound showed no significant inhibition, with IC 50 > 30 μM in all five isoforms (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) …”

“…The volume of distribution was moderate, from 1.1 to 3.9 L/kg across all species evaluated, and is consistent with the zwitterionic character of the molecule and the second basic center (Tables and ). Taken together, it had suitable PK properties for progression into clinical trials …”

“…Treatment with 18 caused a dose-dependent decrease in tumor volume with no tolerance issues. It shows 46% and 96% TGI for 15 mg/kg and 50 mg/kg dose, respectively …”

Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity

“…UPLC−MS: 1.49 min, purity >95%; MS (ESI) m/z: calcd, 792.41 for C 49 H 53 N 5 O 5 [M + H] + ; found, 792.5; 1 H NMR (400 MHz, MeOD): δ 7.93 (s, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.17−7.09 (m, 3H), 6.84 (dd, J = 7.5, 1.7 Hz, 2H), 6.72− 6.60 (m, 4H), 6.53 (dd, J = 8.3, 2.6 Hz, 1H), 5.17 (dd, J = 12.6, 5.4 Hz, 1H), 4.94 (s, 4H), 4.37 (d, J = 5.3 Hz, 1H), 3.82−3.58 (m, 4H), 3.56− 3.41 (m, 5H), 3.24−2.97 (m, 6H), 2.94−2.66 (m, 3H), 2.41−2.10 (m, 8H), 1.88−1.70 (m, 5H). (21). A mixture of intermediate 48 (500 mg, 1.0 equiv), methyl azetidine-3-carboxylate hydrochloride (232 mg, 2.0 equiv), Pd(OAc) 2 (34 mg, 0.2 equiv), BINAP (143 mg, 0.3 equiv), and Cs 2 CO 3 (996 mg, 4.0 equiv) in toluene (15 mL) was degassed and purged with 3 times N 2 , and the reaction was stirred at 100 °C under a N 2 atmosphere for 16 h. After cooling to rt, the reaction mixture was diluted with DCM and filtered through Celite to remove insoluble catalyst and salts, and the filter cake was washed with DCM.…”