Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs).

In this study, we have developed new classes of SERDs that contain the OBHSA core structure and different side chains, e.g., basic side chains, long alkyl acid side chains, and glycerol ether side chains, to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds. These novel SERDs could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy. Among the SERDs, compounds 17d, 17e and 17g containing a basic side chain with a N-trifluoroethyl substituent and a para methoxyl group at the phenyl group of the sulfonamide turned out to be the best candidates for ER degraders. A further docking study of these compounds with ERα elucidates their structure-activity relationships, which provides guidance to design new PROTAC degrons targeting ER for breast cancer therapy. Lastly, easy modification of these PROTAC-like SERDs enables further fine-tuning of their pharmacokinetic properties, including oral availability. PMID: 30939353 [PubMed - as supplied by publisher]
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research