我AZD-8542(AZD-8542) - 药物靶点：SMO

概要基本信息药物类型小分子化药别名AZD-8542、AZD8542靶点SMO作用方式拮抗剂作用机制SMO拮抗剂(SMO受体拮抗剂)治疗领域肿瘤在研适应症-非在研适应症转移性基底细胞癌原研机构AstraZeneca PLC在研机构-非在研机构AstraZeneca PLC权益机构-最高研发阶段无进展临床前首次获批日期-最高研发阶段(中国)-特殊审评-关联100 项与 AZD-8542 相关的临床结果登录后查看更多信息100 项与 AZD-8542 相关的转化医学登录后查看更多信息100 项与 AZD-8542 相关的专利（医药）登录后查看更多信息4 项与 AZD-8542 相关的文献（医药）2023-03-01·Biochemistry and biophysics reportsCombined treatments with AZD5363, AZD8542, curcumin or resveratrol induce death of human glioblastoma cells by suppressing the PI3K/AKT and SHH signaling pathwaysArticle作者: Romero-Trejo, Daniel ; Mejía-Rodríguez, Rosalinda ; González, Rosa O ; Segovia, José Glioblastoma (GBM) is a very aggressive tumor that presents vascularization, necrosis and is resistant to chemotherapy and radiotherapy. Current treatments are not effective eradicating GBM, thus, there is an urgent need to develop novel therapeutic strategies against GBM. AZD5363, AZD8542, curcumin and resveratrol, are widely studied for the treatment of cancer and in the present study we explored the effects of the administration of combined treatments with AZD5363, AZD8542, curcumin or resveratrol on human GBM cells. We found that the combined treatments with AZD5363+AZD8542+Curcumin and AZD8542+Curcumin+Resveratrol inhibit the PI3K/AKT and SHH survival pathways by decreasing the activity of AKT, the reduction of the expression of SMO, pP70S6k, pS6k, GLI1, p21 and p27, and the activation of caspase-3 as a marker of apoptosis. These results provide evidence that the combined treatments AZD5363+AZD8542+Curcumin and AZD8542+Curcumin+Resveratrol have the potential to be an interesting option against GBM.2022-01-01·European journal of cancer (Oxford, England : 1990)1区 · 医学Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer1区 · 医学Article作者: Pineda-Villegas, Priscila ; Ávila-Moreno, Federico ; Peralta-Arrieta, Irlanda ; Arrieta, Oscar ; Zúñiga, Joaquín ; Trejo-Villegas, Octavio A ; Mendoza-Milla, Criselda ; González-López, Marco A ; Ortiz-Quintero, Blanca ; Zatarain-Barrón, Zyanya L ; Ordóñez-Luna, María Del Carmen ; Ceja-Rangel, Hugo A ; Armas-López, Leonel BACKGROUND:Mesenchyme homeobox-2 (MEOX2)-mediated regulation of glioma-associated oncogene-1 (GLI1) has been associated with poor overall survival, conferring chemoresistance in lung cancer. However, the role of MEOX2/GLI1 in resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based therapy remains unexplored in human lung cancer.METHODS:Functional assays using genetic silencing strategy by short hairpin RNAs, as well as cytotoxic (tetrazolium dye MTT) and clonogenic assays, were performed to evaluate MEOX2/GLI1-induced malignancy capacity in lung cancer cells. Further analysis performed includes western blot, qPCR and ChIP-qPCR assays to identify whether MEOX2/GLI1 promote EGFR/AKT/ERK activation, as well as EGFR overexpression through epigenetic mechanisms. Finally, preclinical tumour progression in vivo and progression-free disease interval analyses in patients treated with EGFR-TKI were included.RESULTS:Overexpressed MEOX2/GLI1 in both EGFR wild-type and EGFR/KRAS-mutated lung cancer cells were detected and involved in the activation/expression of EGFR/AKT/ERK biomarkers. In addition, MEOX2/GLI1 was shown to be involved in the increased proliferation of tumour cells and resistance capacity to cisplatin, EGFR-TKIs (erlotinib and AZD9291 'osimertinib'), AZD8542-SMO, and AZD6244-MEKK1/2. In addition, we identified that MEOX2/GLI1 promote lung tumour cells progression in vivo and are clinically associated with poorer progression-free disease intervals. Finally, both MEOX2 and GLI1 were detected to be epigenetically involved in EGFR expression by reducing both repressive markers polycomb-EZH2 and histone H3K27me3, but, particularly, increasing an activated histone profile H3K27Ac/H3K4me3 at EGFR-gene enhancer-promoter sequences that probably representing a novel EGFR-TKI-based therapy resistance mechanism.CONCLUSION:MEOX2/GLI1 promote resistance to cisplatin and EGFR-TKI-based therapy in lung cancer cells, modulating EGFR/AKT/ERK signalling pathway activation, as well as inducing an aberrant epigenetic modulation of the EGFR-gene expression in human lung cancer.2020-01-01·Bioorganic & medicinal chemistry3区 · 医学Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2- pyridylmethoxy)benzamide (AZD7254)3区 · 医学Article作者: Zheng, Xiaolan ; Su, Qibin ; Bodnarchuk, Michael S ; Yang, Bin ; Dakin, Les ; Brassil, Patrick ; Redmond, Sean ; Hird, Alexander W ; Hattersley, Maureen M ; John Russell, Daniel ; Godin, Robert ; Janetka, James W ; Daly, Kevin Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.100 项与 AZD-8542 相关的药物交易登录后查看更多信息研发状态10 条进展最快的记录, 登录 后查看更多信息适应症最高研发状态国家/地区公司日期转移性基底细胞癌临床前美国 AstraZeneca PLC2020-01-01转移性基底细胞癌临床前英国 AstraZeneca PLC2020-01-01登录后查看更多信息临床结果适应症分期评价查看全部结果研究分期人群特征评价人数分组结果评价发布日期 No Data

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