治疗癌症及抗纤维化的新靶标的鉴定（英文）
本文选题：protein-protein 切入点：interactions 出处：《中国药理学与毒理学杂志》2017年10期
【摘要】：Gene transcription mechanisms are critical control points for cell function and differentiation as well as disease pathology.It has remained difficult to target gene transcription mechanisms with small molecule drugs due in part to the role of protein-protein interactions in transcription complexes.Rho A/C-GTPase regulation of the serum responsive transcription factor complex involving serum response factor(SRF)and myocardin-related transcription factor(MRTF)plays a key role in cancer and fibrotic mechanisms.In an attempt to disrupt this critical gene transcription mechanism,we undertook a high-throughput "pathway screen" using an SRE-Luciferase reporter which was activated by transient transfection of HEK293 cells with Ga13,an up-stream activator of Rho A and Rho C.The Rho/MRTF inhibitor tool compound CCG-1423 was identified in this screen.It and analogs such as CCG-203971have been used extensively to disrupt myofibroblast activation and tissue fibrosis as well as melanoma cell migration and metastasis.In the present study,we have used immobilized compounds and mass spectroscopy to identify the molecular target of the CCG-203971 series of anti-fibrotic and anti-metastatic agents.It is a poorly studied intranuclear protein that participates in gene transcription regulation by NF-κB and MRTF/SRF mechanisms.This dual mechanism rationalizes the strong efficacy of CCG-203971 and related compounds as anti-fibrotic and anti-metastatic agents.The identification of a molecular target also greatly facilitates future compound development through structure-based drug discovery and target biology evaluation.
[Abstract]:Gene transcription mechanisms are critical control points for cell function and differentiation as well as disease pathology.It has remained difficult to target gene transcription mechanisms with small molecule drugs due in part to the role of protein-protein interactions in transcription complexes.Rho A/C-GTPase regulation of the serum responsive transcription factor complex involving serum response factor(SRF)and myocardin-related transcription factor(MRTF)plays a key role in cancer and fibrotic mechanisms.In an attempt to disrupt this. Critical gene transcription mechanismwe undertook a "pathway screen" using an SRE-Luciferase reporter which was activated by transient transfection of HEK293 cells with Ga13an up-stream activator of Rho A and Rho inhibitor tool compound compound CCG-1423 identified in this and and and extensively extensively as been extensively to disrupt myofibroblast activation activation and #en4question as #en4as high-throughput as high-throughput cell cell and and and the present present present. Immobilized compounds and mass spectroscopy to identify the molecular target of the CCG-203971 series of anti-fibrotic and anti-metastatic agents.It is a poorly studied studied studied intranuclear protein that participates in gene regulation by-魏 B and MRTF/SRF mechanisms.This dual dual rationalizes strong strong of anti-fibrotic compounds as anti-fibrotic and anti-metastatic identification of a molecular identification identification identification of a molecular facilitates facilitates compound through through structure-based structure-based structure-based #en657# biology #enevaluation.
【作者单位】： Department
【基金】：supported by NIH grants R01 AR066049(to SD Larsen) and R01 GM115459(to RRN)
【分类号】：R91
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