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. Epub 2020 Oct 6.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Indoles / administration & dosage
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • MCF-7 Cells
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Receptors, Estrogen / antagonists & inhibitors*
  • Receptors, Estrogen / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Indoles
  • Receptors, Estrogen
  • indole