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

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.

01 Oct 2021·Endocrine-Related CancerQ2 · MEDICINE

Development of improved SRC-3 inhibitors as breast cancer therapeutic agents

Q2 · MEDICINE

Article

Author: Cardenas, David ; Jain, Prashi ; Lu, Dong ; Qin, Li ; Xu, Jianming ; Wang, Jin ; Lonard, David M ; Peng, Xiaohui ; O’Malley, Bert W ; Yu, Xiaobin ; Yu, Yang ; Chen, Jianwei

Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in its progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes, which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial–mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high-throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs are synthesized that incorporate the addition of F atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5–50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress the growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells, respectively, SI-10 and SI-12 effectively inhibited the progression of breast cancer lung metastasis. These results demonstrate that SI-10 and SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases.

01 Jul 2008·Food ChemistryQ1 · AGRICULTURAL & FORESTRY SCIENCE

Enrichment of isoflavone aglycones in soymilk by fermentation with single and mixed cultures of Streptococcus infantarius 12 and Weissella sp. 4

Q1 · AGRICULTURAL & FORESTRY SCIENCE

Article

Author: Kim, Jong Sang ; Chun, Jiyeon ; Kim, Jeong Hwan

Soymilk was fermented with either Streptococcus infantarius 12 (Si 12), Weissella sp. 4 (Ws 4), or their mixed cultures with different mixing ratios (Si 12:Ws 4=1:1, 1:3, 1:5, and 1:10, v/v) for 12h at 37°C. All cultures in soymilk readily proliferated and reached about 10(8-9)CFU/mL. After 12h, pH and titratable acidity of soymilk ranged 4.19-4.47 and 0.57%-0.64%, respectively. The pH of soymilk fermented with Si 12 was the lowest while that obtained with Ws 4 the highest. A sharp increase in β-glucosidase (β-glu) activity corresponded well with a rapid decrease in isoflavone glucosides and an increase in aglycone contents. The rate of hydrolysis of isoflavone glucosides was the least with Si 12 while the highest with Ws 4, resulting in about 23%-33% and 98%-99% hydrolysis of the glucosides with Si 12 and Ws 4, respectively, after 12h. Mixed cultures with 1:3, 1:5, and 1:10 ratios seem to be more effective starters for bioactive fermented soymilk with more aglycones and appropriate acidity in a short time than single cultures.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	Coactigon, Inc.	-
Neoplasms	Discovery	US	Baylor College of Medicine	29 Mar 2024

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