Vps34 inhibitors(Genentech)(Vps34 inhibitors(Genentech)) - 药物靶点：Vps34_在研适应症：糖尿病_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Compound 5

靶点

Vps34

作用机制

Vps34抑制剂(phosphatidylinositol 3-kinase catalytic subunit type 3 inhibitors)

治疗领域

内分泌与代谢疾病

在研适应症

糖尿病

非在研适应症-

原研机构

Genentech, Inc.

在研机构

Genentech, Inc.

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C14H20N4O2

InChIKeyLQBRZKIUSVUXJP-OUAUKWLOSA-N

CAS号2770104-92-0

关联

100 项与 Vps34 inhibitors(Genentech) 相关的临床结果

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100 项与 Vps34 inhibitors(Genentech) 相关的转化医学

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100 项与 Vps34 inhibitors(Genentech) 相关的专利（医药）

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6

项与 Vps34 inhibitors(Genentech) 相关的文献（医药）

2024-11-01·Biomolecules & Therapeutics

Regulatory Mechanisms Governing the Autophagy-Initiating VPS34 Complex and Its inhibitors

Review

作者: Lee, Gi Jeong ; Lee, Yongook ; Park, Jung Ho ; Lee, Chang Hoon ; Kim, Boram ; Tuan, Nguyen Minh

VPS34 is a crucial protein in cells, essential for handling cellular stress through its involvement in autophagy and endocytosis. This protein functions as a Class III phosphatidylinositol 3-kinase, producing phosphatidylinositol 3-phosphate, which is necessary for autophagy and vesicle trafficking. Additionally, VPS34 forms two mutually exclusive complexes, each playing a vital role in autophagy and endocytic sorting. These complexes share common subunits, including VPS15, VPS34, and Beclin 1, with complex I having ATG14 as a specific subunit. Due to its association with various human diseases, regulation of the VPS34 complex I has garnered significant interest, emerging as a potential therapeutic target for drug discovery. Summaries of the structure, function of VPS34 complexes, and developed VPS34 inhibitors have been provided, along with discussions on the regulation mechanism of VPS34, particularly in relation to the initiation complex I of autophagy. This offers valuable insights for treating autophagy-related diseases.

2024-09-27·CURRENT MEDICINAL CHEMISTRY

Phenolic Glycoside Monomer from Reed Rhizome Inhibits Melanin Production via PI3K-Akt and Ras-Raf-MEK-ERK Pathways

Article

作者: Bao, Kechen ; Xu, Ruitian ; Xi, Rongjiao ; He, Runnan ; Yao, Hong ; Peng, Rui ; Ming, Dong ; Liu, Xiuyun ; Su, Yanfang ; Pang, Meijun ; Zhi, Hui ; Zhang, Kuo ; Du, Yunfei

Introduction::

Melanogenesis, the process responsible for melanin production, is a critical determinant of skin pigmentation. Dysregulation of this process can lead to hyperpigmentation disorders.

Method::

In this study, we identified a novel Reed Rhizome extract, (1'S, 2'S)-syringyl glycerol 3'-O-β-D-glucopyranoside (compound 5), and evaluated its anti-melanogenic potential in zebrafish models and in vitro assays. Compound 5 inhibited melanin synthesis by 36.66% ± 14.00% and tyrosinase in vivo by 48.26% ± 6.94%, surpassing the inhibitory effects of arbutin. Network pharmacological analysis revealed key targets, including HSP90AA1, HRAS, and PIK3R1, potentially involved in the anti-melanogenic effects of compound 5.

Results::

Molecular docking studies supported the interactions between compound 5 and these targets. Further, gene expression analysis in zebrafish indicated that compound 5 up-regulates hsp90aa1.1, hrasa, and pik3r1, and subsequently down-regulating mitfa, tyr, and tyrp1, critical genes in melanogenesis.

Conclusion::

These findings suggest that compound 5 inhibits melanin production via PI3K-Akt and Ras-Raf-MEK-ERK signaling pathways, positioning it as a promising candidate for the treatment of hyperpigmentation.

2021-11-01·INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS

Mitophagy Induction by ROS-PINK1 Signaling Protects Head and Neck Cancer From Radiotherapy

Article

作者: Gurel, Z ; Nickel, K P ; Kimple, R J ; Lee, Y S ; Bradley, S T

PURPOSE/OBJECTIVE(S):

Approximate 25% of patients with local advanced head and neck cell carcinoma (HNSCC) treated with radiation still suffer from local relapse and are considered radiation resistant. We previously determined that radiation induces autophagy, a pro-survival cellular stress response, in HNSCC. In this study, we examine the consequence of autophagy inhibition and investigate the molecular mechanism underlying RT-induced autophagy.

MATERIALS/METHODS:

Autophagy was assessed using a nano-Luc LC3 reporter assay (Promega), immunoblotting and immunofluorescence for LC3 and acridine orange in multiple HNSCC cell lines. RNAi knockdown of EGFR, LAPTM4B and PINK1 were used to test the involved signaling molecules. CM-H2DCFDA was used as a measure of reactive oxygen species (ROS). Hydrogen peroxide was used to stimulate ROS production. Trolox, a ROS scavenger, was used to determine the correlation between ROS and RT-induced autophagy. Mitophagy determination was completed by using MitoTracker Red (Invitrogen) combined with immunofluorescence staining for LC3 and immunoblotting. Radiation was delivered using a RS225 cabinet irradiator at a dose rate of approximately 3 Gy/min with dose validation by TLD using custom, geometry specific phantoms. SAR405, a VPS34 inhibitor, was used to inhibit autophagy. A flank xenograft model using A253 cells was used to test the combination of autophagy inhibitors and radiotherapy in vivo.

RESULTS:

RT caused a two-fold increase in autophagy as assessed using the reporter assay and immunoblotting. Knockdown of EGFR and LAPTM4B, two proteins important in growth-factor deprivation induced autophagy, did not influence autophagy in RT-treated cells. RT did increase the accumulation of ROS (∼50%) and the dephosphorylation of mTOR (∼25%). Addition of Trolox to RT contributed to a considerable decrease in both ROS (∼50%) and autophagy (∼50%). RT also resulted in a mRNA elevation of PINK1 (∼1.6 fold), a mitochondrial modulator. Immunoblotting for LC3 in both the cytoplasmic and mitochondrial fraction indicated RT mostly increases mitophagy rather than bulk autophagy, which was confirmed using immunofluorescent staining for LC3 and MitoTracker red. Using a clonogenic survival assay, the combination of SAR405 and RT resulted in complete loss of cell survival suggesting a radiosensitizing effect. In vivo, SAR405 treatment combined with RT improved tumor control when compared to RT or SAR405 alone.

CONCLUSION:

RT-induced mitophagy involves ROS-PINK1 pathway and the regulation of mTOR. Inhibition of autophagy resulted in decreased cell survival in vitro and decreased in vivo tumor growth. These results suggest that targeting mitophagy may be a viable approach to sensitize HNSCC to radiation treatment.

100 项与 Vps34 inhibitors(Genentech) 相关的药物交易

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