Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD)

  • Bioorg Med Chem Lett. 2022 Jun 15;66:128734. doi: 10.1016/j.bmcl.2022.128734.
Jianyu Lu  1 ,  Chi-Chung Chan  2 ,  Deheng Sun  2 ,  Guoping Hu  2 ,  Huijun He  1 ,  Jian Li  2 ,  Jiaqiang Dong  3 ,  Kai Liu  3 ,  Liang Shen  2 ,  Lihong Hu  1 ,  Qingyang Gu  2 ,  Shuhui Chen  2 ,  Tielin Wang  3 ,  Ting Gong  3 ,  Wei Tang  3 ,  Xiaoting Li  1 ,  Xiaotong Zhu  3 ,  Xu Zeng  1 ,  Yingjie Zhu  2 ,  Yuanfeng Xia  2 ,  Yuanyuan Huang  2 ,  Yusong Zhu  2 ,  Zhenteng Liu  3 ,  Charles Z Ding  4
Affiliations
  • 1. WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
  • 2. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3. 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.
  • 4. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China. Electronic address: [email protected].
PMID: 35436589 DOI: 10.1016/j.bmcl.2022.128734
Abstract

We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast Cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).

Keywords
Estrogen receptor; Indole; SERD.
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