更新于：2024-11-01

CDC7 x CDK9

更新于：2024-11-01

基本信息

关联

项与 CDC7 x CDK9 相关的药物

NMS-1116354

靶点

CDC7 x CDK9

作用机制

CDC7抑制剂 [+1]

在研机构-

原研机构

Nerviano Medical Sciences S.r.l

在研适应症-

非在研适应症

晚期恶性实体瘤 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 CDC7 x CDK9 相关的临床试验

NCT01092052 / Terminated临床1期

A Phase I Dose-Escalation Study of NMS-1116354 in Adult Patients With Advanced/Metastatic Solid Tumors

The purpose of this study is to evaluate the safety profile of NMS-1116354, a CDC7 kinase inhibitor, in adult patients with advanced/metastatic solid tumors.

开始日期2010-01-01

申办/合作机构

Nerviano Medical Sciences S.r.l

NCT01016327 / Terminated临床1期

A Phase I Dose-Escalation Study of NMS-1116354 in Adult Patients With Advanced Solid Tumors

The purpose of this study is to evaluate the safety profile of NMS-1116354, a CDC7 kinase inhibitor, in adult patients with advanced solid tumors.

开始日期2009-04-01

申办/合作机构

Nerviano Medical Sciences S.r.l

100 项与 CDC7 x CDK9 相关的临床结果

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100 项与 CDC7 x CDK9 相关的转化医学

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0 项与 CDC7 x CDK9 相关的专利（医药）

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项与 CDC7 x CDK9 相关的文献（医药）

2024-02-01·Cell Genomics

Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy

Article

作者: Saunders, Lauren ; Monnat, Raymond J ; Gasperini, Molly ; Trapnell, Cole ; Hill, Andrew J ; Regalado, Samuel G ; Jackson, Dana L ; Shendure, Jay ; McFaline-Figueroa, José L ; Srivatsan, Sanjay ; Alvarez, Sarai ; Lazarchuck, Paul ; Domcke, Silvia

Chemical genetic screens are a powerful tool for exploring how cancer cells' response to drugs is shaped by their mutations, yet they lack a molecular view of the contribution of individual genes to the response to exposure. Here, we present sci-Plex-Gene-by-Environment (sci-Plex-GxE), a platform for combined single-cell genetic and chemical screening at scale. We highlight the advantages of large-scale, unbiased screening by defining the contribution of each of 522 human kinases to the response of glioblastoma to different drugs designed to abrogate signaling from the receptor tyrosine kinase pathway. In total, we probed 14,121 gene-by-environment combinations across 1,052,205 single-cell transcriptomes. We identify an expression signature characteristic of compensatory adaptive signaling regulated in a MEK/MAPK-dependent manner. Further analyses aimed at preventing adaptation revealed promising combination therapies, including dual MEK and CDC7/CDK9 or nuclear factor κB (NF-κB) inhibitors, as potent means of preventing transcriptional adaptation of glioblastoma to targeted therapy.

2020-07-01·Journal of Molecular Neuroscience3区 · 医学

Targeting Inflammation, PHA-767491 Shows a Broad Spectrum in Protein Aggregation Diseases

3区 · 医学

Article

作者: Hsieh-Li, Hsiu Mei ; Chang, Ya-Ching ; Sun, Ying-Chieh ; Lee, Guan-Chiun ; Lee-Chen, Guey-Jen ; Huang, Hsin-Yu ; Lin, Chia-Wei ; Huang, Hei-Jen ; Chen, Shu-Ling ; Chung, Yu-Han

Many protein aggregation diseases (PAD) affect the nervous system. Deposits of aggregated disease-specific proteins are found within or around the neuronal cells of neurodegenerative diseases. Although the main protein component is disease-specific, oligomeric aggregates are presumed to be the key agents causing the neurotoxicity. Evidence has shown that protein aggregates cause a chronic inflammatory reaction in the brain, resulting in neurodegeneration. Therefore, strategies targeting anti-inflammation could be beneficial to the therapeutics of PAD. PHA-767491 was originally identified as an inhibitor of CDC7/CDK9 and was found to reduce TDP-43 phosphorylation and prevent neurodegeneration in TDP-43 transgenic animals. We recently identified PHA-767491 as a GSK-3β inhibitor. In this study, we established mouse hippocampal primary culture with tau-hyperphosphorylation through the activation of GSK-3β using Wortmannin and GF109203X. We found that PHA-767491 significantly improved the neurite outgrowth of hippocampal primary neurons against the neurotoxicity induced by GSK-3β. We further showed that PHA-767491 had neuroprotective ability in hippocampal primary culture under oligomeric Aβ treatment. In addition, PHA-767491 attenuated the neuroinflammation in mouse cerebellar slice culture with human TBP-109Q agitation. Further study of SCA17 transgenic mice carrying human TBP-109Q showed that PHA-767491 ameliorated the gait ataxia and the inflammatory response both centrally and peripherally. Our findings suggest that PHA-767491 has a broad spectrum of activity in the treatment of different PAD and that this activity could be based on the anti-inflammation mechanism.

2019-12-01·Breast Cancer Research1区 · 医学

A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy

1区 · 医学

ArticleOA

作者: Zhang, Yinghui ; McLaughlin, Ronan P ; Smid, Marcel ; Foekens, John A ; van der Noord, Vera E ; He, Jichao ; Martens, John W M ; Redel, Jevin ; van de Water, Bob

BACKGROUNDThe effective treatment of triple-negative breast cancer (TNBC) remains a profound clinical challenge. Despite frequent epidermal growth factor receptor (EGFR) overexpression and reliance on downstream signalling pathways in TNBC, resistance to EGFR-tyrosine kinase inhibitors (TKIs) remains endemic. Therefore, the identification of targeted agents, which synergise with current therapeutic options, is paramount.METHODSCompound-based, high-throughput, proliferation screening was used to profile the response of TNBC cell lines to EGFR-TKIs, western blotting and siRNA transfection being used to examine the effect of inhibitors on EGFR-mediated signal transduction and cellular dependence on such pathways, respectively. A kinase inhibitor combination screen was used to identify compounds that synergised with EGFR-TKIs in TNBC, utilising sulphorhodamine B (SRB) assay as read-out for proliferation. The impact of drug combinations on cell cycle arrest, apoptosis and signal transduction was assessed using flow cytometry, automated live-cell imaging and western blotting, respectively. RNA sequencing was employed to unravel transcriptomic changes elicited by this synergistic combination and to permit identification of the signalling networks most sensitive to co-inhibition.RESULTSWe demonstrate that a dual cdc7/CDK9 inhibitor, PHA-767491, synergises with multiple EGFR-TKIs (lapatinib, erlotinib and gefitinib) to overcome resistance to EGFR-targeted therapy in various TNBC cell lines. Combined inhibition of EGFR and cdc7/CDK9 resulted in reduced cell proliferation, accompanied by induction of apoptosis, G2-M cell cycle arrest, inhibition of DNA replication and abrogation of CDK9-mediated transcriptional elongation, in contrast to mono-inhibition. Moreover, high expression of cdc7 and RNA polymerase II Subunit A (POLR2A), the direct target of CDK9, is significantly correlated with poor metastasis-free survival in a cohort of breast cancer patients. RNA sequencing revealed marked downregulation of pathways governing proliferation, transcription and cell survival in TNBC cells treated with the combination of an EGFR-TKI and a dual cdc7/CDK9 inhibitor. A number of genes enriched in these downregulated pathways are associated with poor metastasis-free survival in TNBC.CONCLUSIONSOur results highlight that dual inhibition of cdc7 and CDK9 by PHA-767491 is a potential strategy for targeting TNBC resistant to EGFR-TKIs.