2. Academic Validation
  3. Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy

Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy

  • J Med Chem. 2024 Apr 11;67(7):5333-5350. doi: 10.1021/acs.jmedchem.3c01596.
Dong Lu 1,  Jianwei Chen 1,  Li Qin 2,  Imani Bijou 1,  Ping Yi 3 4,  Feng Li 3 5,  Xianzhou Song 1,  Kevin R MacKenzie 3 5,  Xin Yu 1,  Bin Yang 1,  Sandipan Roy Chowdhury 1,  James D Korp 6,  Bert W O'Malley 2,  David M Lonard 2,  Jin Wang 1 2
Affiliations

Affiliations

  • 1 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 3 Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 4 Department of Biology and Biochemistry, University of Houston, Houston, Texas 77205, United States.
  • 5 Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.
  • 6 Department of Chemistry, University of Houston, Houston, Texas 77204, United States.
PMID: 38551814 DOI: 10.1021/acs.jmedchem.3c01596
Abstract

Steroid receptor coactivator 3 (SRC-3) is a critical mediator of many intracellular signaling pathways that are crucial for Cancer proliferation and metastasis. In this study, we performed structure-activity relationship exploration and drug-like optimization of the hit compound SI-2, guided by in vitro/in vivo metabolism studies and cytotoxicity assays. Our efforts led to the discovery of two lead compounds, SI-10 and SI-12. Both compounds exhibit potent cytotoxicity against a panel of human Cancer cell lines and demonstrate acceptable pharmacokinetic properties. A biotinylated estrogen response element pull-down assay demonstrated that SI-12 could disrupt the recruitment of SRC-3 and p300 in the Estrogen Receptor complex. Importantly, SI-10 and SI-12 significantly inhibited tumor growth and metastasis in vivo without appreciable acute toxicity. These results demonstrate the potential of SI-10 and SI-12 as drug candidates for Cancer therapy, given their potent SRC-3 inhibition and promising pharmacokinetic and toxicity profiles.

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