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

Authors

Dong Lu
Jianwei Chen
Li Qin
Imani Bijou
Ping Yi
Feng Li
Xianzhou Song
Kevin R MacKenzie
Xin Yu
Bin Yang
Sandipan Roy Chowdhury
James D Korp
Bert W O'Malley
David M Lonard
Jin Wang

Publication Date

4-11-2024

Journal

Journal of Medicinal Chemistry

DOI

10.1021/acs.jmedchem.3c01596

PMID

38551814

PMCID

PMC11105966

PubMedCentral® Posted Date

5-20-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Nuclear Receptor Coactivator 3, Cell Line, Structure-Activity Relationship, Neoplasms, Signal Transduction, Cell Proliferation, Cell Line, Tumor, Antineoplastic Agents, steroid receptor coactivator, small-molecule inhibitor, drug-like optimization, lead compounds

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 (SAR) 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 (ERE) pull-down assay demonstrated that SI-12 could disrupt the recruitment of SRC-3 and p300 in the ER 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.