Design, syntheses and evaluations of novel indole derivatives as orally selective estrogen receptor degraders (SERD)

  • Bioorg Med Chem Lett. 2020 Nov 15;30(22):127601. doi: 10.1016/j.bmcl.2020.127601.
Jiaqiang Dong  1 ,  Tie-Lin Wang  1 ,  Jianyu Lu  2 ,  Charles Z Ding  3 ,  Lihong Hu  4 ,  Guoping Hu  3 ,  Huijun He  4 ,  Xu Zeng  4 ,  Xiaoting Li  4 ,  Deheng Sun  3 ,  Yingjie Zhu  3 ,  Liang Shen  3 ,  Qingyang Gu  3 ,  Chi-Chung Chan  3 ,  Yuanfeng Xia  3 ,  Jian Li  3 ,  Shuhui Chen  3
Affiliations
  • 1. Luoxin Pharmaceutical (Shanghai) Co., Ltd., Building 1 and 1st-3rd Floors, Building 2, No.85 Faladi Road, China (Shanghai) Pilot Free Trade Zone, Shanghai 201210, China.
  • 2. WuXi AppTec (Wuhan), 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China. Electronic address: [email protected].
  • 3. WuXi AppTec (Headquarters), 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 4. WuXi AppTec (Wuhan), 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
PMID: 33035677 DOI: 10.1016/j.bmcl.2020.127601
Abstract

Most Estrogen Receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + Breast Cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection. In this paper, we report herein a novel indole series compounds with nanomolar range ER degradation potencies and oral systemic exposures. Selected compounds suppressed tumor growth in vivo in ER + MCF7 Breast Cancer CDX model via p.o. administration. All those data supported further optimizations of this analog to develop preclinical candidate as oral SERD for ER + breast cancer's treatment.

Keywords
Estrogen receptor; Indole; SERD.