当前位置:
X-MOL 学术
›
Endocr. Relat. Cancer
›
论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Development of improved SRC-3 inhibitors as breast cancer therapeutic agents.
Endocrine-Related Cancer ( IF 3.9 ) Pub Date : 2021-08-13 , DOI: 10.1530/erc-20-0402 Li Qin 1 , Jianwei Chen 2 , Dong Lu 2 , Prashi Jain 1 , Yang Yu 1 , David Cardenas 1 , Xiaohui Peng 1 , Xiaobin Yu 1 , Jianming Xu 1 , Jin Wang 2 , Bert W O'Malley 1 , David M Lonard 1
Endocrine-Related Cancer ( IF 3.9 ) Pub Date : 2021-08-13 , DOI: 10.1530/erc-20-0402 Li Qin 1 , Jianwei Chen 2 , Dong Lu 2 , Prashi Jain 1 , Yang Yu 1 , David Cardenas 1 , Xiaohui Peng 1 , Xiaobin Yu 1 , Jianming Xu 1 , Jin Wang 2 , Bert W O'Malley 1 , David M Lonard 1
Affiliation
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.
中文翻译:
开发改进的 SRC-3 抑制剂作为乳腺癌治疗剂。
类固醇受体共激活剂 (SRC) 在癌症的发生及其进展为更具侵袭性的疾病中具有特定和独特的致癌作用。这些共激活因子与核受体和其他转录因子相互作用以促进多个基因的转录,从而增强癌细胞的增殖、迁移、侵袭、肿瘤血管生成和上皮-间质转化 (EMT)。使用小分子抑制剂 (SMI) 靶向 SRC 是控制癌症进展和转移的一种有前途的方法。通过高通量筛选分析,我们最近将 SI-2 鉴定为有效的 SRC SMI。为了开发治疗剂 SI-10 和 SI-12,合成了 SI-2 类似物,在 SI-2 化学结构中加入了 F 原子。因此,这些类似物表现出显着延长的血浆半衰期、最小的毒性和提高的 hERG 活性。生物学功能分析表明,SI-10 和 SI-12 处理 (5-50 nM) 可显着抑制体外乳腺癌细胞的活力、迁移和侵袭,并抑制乳腺癌 PDX 类器官的生长。用 10 mg/kg/天的 SI-10 或 SI-12 治疗小鼠足以抑制源自 MDA-MB-231 和 LM2 细胞的异种移植肿瘤的生长。此外,在分别由 MDA-MB-231 和 LM2 细胞开发的自发和实验性转移小鼠模型中,SI-10 和 SI-12 有效地抑制了乳腺癌肺转移的进展。这些结果表明 SI-10 和 SI-12 是有前途的治疗剂,并且在阻断肿瘤转移方面特别有效,
更新日期:2021-07-01
中文翻译:
开发改进的 SRC-3 抑制剂作为乳腺癌治疗剂。
类固醇受体共激活剂 (SRC) 在癌症的发生及其进展为更具侵袭性的疾病中具有特定和独特的致癌作用。这些共激活因子与核受体和其他转录因子相互作用以促进多个基因的转录,从而增强癌细胞的增殖、迁移、侵袭、肿瘤血管生成和上皮-间质转化 (EMT)。使用小分子抑制剂 (SMI) 靶向 SRC 是控制癌症进展和转移的一种有前途的方法。通过高通量筛选分析,我们最近将 SI-2 鉴定为有效的 SRC SMI。为了开发治疗剂 SI-10 和 SI-12,合成了 SI-2 类似物,在 SI-2 化学结构中加入了 F 原子。因此,这些类似物表现出显着延长的血浆半衰期、最小的毒性和提高的 hERG 活性。生物学功能分析表明,SI-10 和 SI-12 处理 (5-50 nM) 可显着抑制体外乳腺癌细胞的活力、迁移和侵袭,并抑制乳腺癌 PDX 类器官的生长。用 10 mg/kg/天的 SI-10 或 SI-12 治疗小鼠足以抑制源自 MDA-MB-231 和 LM2 细胞的异种移植肿瘤的生长。此外,在分别由 MDA-MB-231 和 LM2 细胞开发的自发和实验性转移小鼠模型中,SI-10 和 SI-12 有效地抑制了乳腺癌肺转移的进展。这些结果表明 SI-10 和 SI-12 是有前途的治疗剂,并且在阻断肿瘤转移方面特别有效,