Aminoflavone(Aminoflavone) - 药物靶点：p53_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [2]

靶点

p53

作用机制

p53刺激剂(p53蛋白刺激剂)、细胞凋亡刺激剂

治疗领域

肿瘤皮肤和肌肉骨骼疾病消化系统疾病+ [3]

在研适应症-

非在研适应症

晚期恶性实体瘤复发性乳腺癌ER阳性乳腺癌+ [10]

原研机构

National Cancer Institute

在研机构-

非在研机构

Tigris Pharmaceuticals

National Cancer Institute

Kirax Corp.

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C16H11F3N2O2

InChIKeyRTUZVPPGTJRELI-UHFFFAOYSA-N

CAS号165179-35-1

关联

4

项与 Aminoflavone 相关的临床试验

NCT01233947 / Terminated临床2期

A Randomized Phase II Study of AFP464 +/- Faslodex in ER Positive Breast Cancer Patients Who Had Progressed on Aromatase Inhibitor (AI) Therapy

AFP464 is an investigational agent which may be effective in the treatment of cancer. The purpose of this study is to test the efficacy of AFP464 +/- Faslodex in ER+ breast cancer patients.

开始日期2011-05-01

申办/合作机构

Tigris Pharmaceuticals

NCT01015521 / Withdrawn临床2期

A Two-Arm Open Label Phase II Study of AFP464 (Aminoflavone Prodrug) in Previously-treated ER-positive or Triple-negative Breast Cancer Patients

This is a phase II study to assess the efficacy of Aminoflavone prodrug in triple negative and ER+ breast cancer.

开始日期2010-04-01

申办/合作机构

Tigris Pharmaceuticals

NCT00348699 / Completed临床1期IIT

A Phase I Study and Pharmacological Trial of Once Weekly Aminoflavone Prodrug (AFP464) Administered 3 Out of Every 4 Weeks in Solid Tumor Patients

This phase I trial studies the side effects and best dose of AFP464 in treating patients with metastatic or refractory solid tumors that cannot be removed by surgery. Drugs used in chemotherapy, such as AFP464, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

开始日期2006-07-01

申办/合作机构

National Cancer Institute

100 项与 Aminoflavone 相关的临床结果

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100 项与 Aminoflavone 相关的转化医学

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100 项与 Aminoflavone 相关的专利（医药）

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36

项与 Aminoflavone 相关的文献（医药）

2023-01-01·Annals of Translational Medicine

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker

Article

作者: Chen, Peng ; Yang, Xian ; Yu, Lingfeng ; Fang, Huipeng ; Chen, Yujie ; Huang, Zhijian ; He, Hao ; Wang, Feng ; Wang, Peiyuan

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase (cGAS) could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on cGAS gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of cGAS in malignant tumors.MethodscGAS expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate cGAS expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes.ResultsCompared to normal tissues, cGAS was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). cGAS expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of cGAS genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with cGAS expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in cGAS expression in vitro. Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. According to the evidence presented above, cGAS may become an important target for cancer therapy.ConclusionsThis study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS, making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.

2020-12-01·Breast Cancer Research1区 · 医学

Identification and targeting of selective vulnerability rendered by tamoxifen resistance

1区 · 医学

ArticleOA

作者: Selivanova, Galina ; Chen, Xinsong ; Peuget, Sylvain ; Zhou, Xiaolei ; Rihani, Ali ; Santos, Gema Sanz ; Hartman, Johan ; Cheng, Qing ; Arnér, Elias S J ; Singh, Madhurendra

AbstractBackgroundThe estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments.Experimental designTo identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity.ResultsHere, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 andInduction ofTumor cellApoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded byTXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo.ConclusionWe have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.

2020-04-01·Cancer Research1区 · 医学

Thermal Proteome Profiling Identifies Oxidative-Dependent Inhibition of the Transcription of Major Oncogenes as a New Therapeutic Mechanism for Select Anticancer Compounds

1区 · 医学

Article

作者: Singh, Madhurendra ; Carlson, Joseph W. ; Zubarev, Roman ; Rihani, Ali ; Hjerpe, Elisabet ; Selivanova, Galina ; Visnes, Torkild ; Shi, Yao ; Joneborg, Ulrika ; Peuget, Sylvain ; Saei, Amir Ata ; Moyano-Galceran, Lidia ; Gaetani, Massimiliano ; Helleday, Thomas ; Hartman, Johan ; Sanz, Gema ; Zhu, Jiawei ; Lehti, Kaisa ; Lindström, Mikael S. ; Chen, Xinsong

AbstractIdentification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFβ, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo. These findings might pave a way for new synthetic lethal combination therapies.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.

100 项与 Aminoflavone 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
ER阳性乳腺癌	临床2期	美国	Tigris Pharmaceuticals	2011-05-01
三阴性乳腺癌	临床2期	-	Tigris Pharmaceuticals	2010-04-01
复发性乳腺癌	临床2期	美国	National Cancer Institute	2006-07-01
原发性腹膜癌	临床2期	美国	National Cancer Institute	2006-07-01
复发性卵巢癌	临床2期	美国	National Cancer Institute	2006-07-01
复发性原发性腹腔癌	临床2期	美国	National Cancer Institute	2006-07-01
晚期恶性实体瘤	临床2期	美国	National Cancer Institute	2006-06-01
转移性实体瘤	药物发现	美国	National Cancer Institute	2006-07-01
卵巢上皮癌	药物发现	美国	National Cancer Institute	2006-07-01
肾细胞癌	药物发现	美国	National Cancer Institute	2006-07-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2011	临床1期	实体瘤	24	AFP464	餘夢齋糧遞範網醖憲鬱(齋繭願蓋鏇鏇壓鹽夢齋) = Pulmonary toxicity is dose limiting 窪窪築憲築構鹽鹽醖鑰 (繭憲襯蓋憲鏇醖夢獵願 )	-	2011-05-20
AACR2009	临床1期	三阴性乳腺癌	-	Vorinostat	蓋廠鏇選鑰鬱顧顧鑰鑰(顧簾窪襯顧夢淵窪壓窪) = 糧願鹹製鏇願觸膚餘鏇製糧廠獵鹹糧觸顧鏇鏇 (願簾膚選膚襯糧襯餘襯 )	-	2009-05-01
AACR2009	临床1期	三阴性乳腺癌	-	Aminoflavone Prodrug	蓋廠鏇選鑰鬱顧顧鑰鑰(顧簾窪襯顧夢淵窪壓窪) = 選願蓋窪範鹹淵齋膚製製糧廠獵鹹糧觸顧鏇鏇 (願簾膚選膚襯糧襯餘襯 )	-	2009-05-01