更新于：2024-11-01

PDPK1

更新于：2024-11-01

基本信息

别名

3-phosphoinositide dependent protein kinase 1、3-phosphoinositide-dependent protein kinase 1、hPDK1

+ [3]

简介

Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.

关联

项与 PDPK1 相关的药物

Tovorafenib

靶点

PDPK1 x Raf kinase

作用机制

PDK1抑制剂 [+1]

在研机构

Day One Biopharmaceuticals, Inc. [+1]

原研机构

Sunesis Pharmaceuticals, Inc.

在研适应症

BRAF 融合或重排阳性的低级别胶质瘤 [+13]

非在研适应症

晚期癌症 [+1]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2024-04-23

PDK1 inhibitors(Amorepacific Corp)

靶点

PDPK1

作用机制

PDK1抑制剂

在研机构

Amorepacific Corp.

原研机构

Amorepacific Corp.

在研适应症

衰老

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

PH-427

靶点

Akt x PDPK1

作用机制

AKT基因抑制剂 [+1]

在研机构

Phusis Therapeutics, Inc.

原研机构

Phusis Therapeutics, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 PDPK1 相关的临床试验

NCT05828069 / Recruiting临床2期IIT

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis

This phase II trial tests the safety, side effects, best dose and activity of tovorafenib (DAY101) in treating patients with Langerhans cell histiocytosis that is growing, spreading, or getting worse (progressive), has come back (relapsed) after previous treatment, or does not respond to therapy (refractory). Langerhans cell histiocytosis is a type of disease that occurs when the body makes too many immature Langerhans cells (a type of white blood cell). When these cells build up, they can form tumors in certain tissues and organs including bones, skin, lungs and pituitary gland and can damage them. This tumor is more common in children and young adults. DAY101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Using DAY101 may be effective in treating patients with relapsed or refractory Langerhans cell histiocytosis.

开始日期2024-03-28

申办/合作机构

National Cancer Institute

NCT06381570 / Recruiting早期临床1期IIT

VICTORY: A Pilot Study to Investigate Safety and Efficacy of Weekly Combination of Intravenous Vinblastine With Oral Type II RAF Inhibitor Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.
The study will be conducted in two sequential phases:
Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later

开始日期2024-03-21

申办/合作机构

The Hospital for Sick Children

[+1]

NCT05566795 / Recruiting临床3期

LOGGIC/FIREFLY-2: a Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients with Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in patients with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring front-line systemic therapy.

开始日期2023-02-27

申办/合作机构

Day One Biopharmaceuticals, Inc.

100 项与 PDPK1 相关的临床结果

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100 项与 PDPK1 相关的转化医学

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0 项与 PDPK1 相关的专利（医药）

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2,728

项与 PDPK1 相关的文献（医药）

2025-05-01·Current Diabetes Reviews

3-Phosphoinositide-Dependent Kinase 1 as a Therapeutic Target for Treating Diabetes

Article

作者: Xumei, Yang ; Jiamin, Zhang ; Jingjin, Liu ; Zihan, Zhang ; Shuya, Pan ; Xiang, Xie

:The role of 3-phosphoinositide-dependent kinase 1 (PDK1) has been welldocumented in the development of diabetes. This review offers a thorough examination of its composition and associated routes, specifically focusing on insulin signaling and glucose processing. By examining the precise connection between PDK1 and diabetes, various strategies specifically targeting PDK1 were also investigated. Additionally, recent discoveries from mouse models were compiled where PDK1 was knocked out in certain tissues, which demonstrated encouraging outcomes for focused treatments despite the absence of any currently approved clinical PDK1 activators. Moreover, the dual nature of PDK1 activation was discussed, encompassing both anti-diabetic and pro-oncogenic effects. Hence, the development of a PDK1 modifier is of utmost importance, as it can activate anti-diabetic pathways while inhibiting pro-oncogenic pathways, thus aiding in the treatment of diabetes. In general, PDK1 presents a noteworthy opportunity for future therapeutic strategies in the treatment of diabetes.

2024-12-31·Cancer Biology & Therapy

CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells

Article

作者: Liu, Shufeng ; Zhang, Liqi ; Lu, Bo ; Chen, Xiaoguang

Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

2024-12-11·Journal of Biomolecular Structure and Dynamics

Insilico molecular modelling to identify PDK-1 targeting agents based on its protein–protein docking interaction

Article

作者: Elango, Kuppanagounder P. ; Vennila, Kailasam N.

PDK1, an attractive cancer target that downstreams 23 other kinases towards cell growth, survival and metabolism has gaining attention due to allosteric effect of ligands bound to it. Generally, the drug design strategy using pharmacophores is either a single protein structure or ensemble or ligand-based. Apart from these methods, yet another new approach of protein-protein docking with state of art computational tool like Schrodinger Suite to generate pharmacophores based on the interacting partners of the protein is proposed in this work. The structure-based pharmacophoric features were picked up from docking the ten interacting partners of PDK1 and screened against the Enamine libraries containing protein-protein interacting compound collection, advanced, protein mimetic and allosteric compounds. High throughput virtual screening against the PIF pocket of PDK1 yields an indole scaffold. The identified indole derivative is proposed to be a strong activator that binds in the protein-protein interaction site of PDK1 which was further confirmed by molecular metadynamics simulations, free energy surface analysis and MM-GBSA calculations. Thus, the pharmacophores generated by the interacting proteins for PPI can facilitate the virtual screening in structure-based drug discovery of similar therapeutic targets.Communicated by Ramaswamy H. Sarma.

项与 PDPK1 相关的新闻（医药）

2024-07-26

·PMLiVE

Ipsen gains ex-US rights to Day One’s brain cancer therapy in deal worth over $460m

Ipsen has announced that it has entered into a global partnership worth over $460m with Day One to commercialise its monotherapy to treat common paediatric brain tumours. As part of the deal, Ipsen will obtain all ex-US global regulatory and commercial rights to tovorafenib for patients living with paediatric low-grade gliomas (pLGG) and any future indications, while Day One maintains exclusive global development and US commercial rights. Under the terms of the agreement, Day One will receive an upfront payment of approximately $111m, including $71m in cash and a $40m equity investment at a premium, along with up to $350m in additional launch and sales milestones, plus tiered royalties. The oral, once-weekly type 2 RAF kinase inhibitor mutant BRAF V600, wild-type BRAF and wild-type CRAF kinases, is indicated in the US under the brand name Ojemda to treat certain patients aged six months and older with relapsed or refractory pLGG. Recognised as the most common brain tumour diagnosed in children, pLGG is a group of slow-growing tumours that can occur in numerous locations throughout the brain and spinal cord. Commenting on the partnership, David Loew, chief executive officer, Ipsen, said: “We are delighted to partner with the team at Day One as we work to bring tovorafenib to every eligible patient around the world who may benefit from this important new treatment option.” Day One’s chief executive officer, Jeremy Bender, said: “Our collaboration with Ipsen… highlights our shared commitment to bring novel therapeutics to patients who have limited treatment options.” Previously granted Orphan Drug Designation by the US Food and Drug Administration, Ojemda recently received approval from the US regulator for patients six months and older with relapsed or refractory pLGG harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation, which accounts for more than 50% of pLGG cases globally. The monotherapy is also currently being evaluated as a therapy for patients aged six months to 25 years with pLGG harbouring BRAF fusion or rearrangement or BRAF V600 mutation requiring front-line treatment as part of the phase 3 FIREFLY-2/LOGGIC study, as well as the FIRELIGHT-1 study, which is investigating tovorafenib in combination with MEK inhibitor pimasertib for adolescent and adult patients with recurrent or progressive solid tumours with MAPK pathway alterations.

孤儿药引进/卖出临床3期临床1期

2024-01-31

·生物探索

Cell Rep Med | 复旦大学余科达/邵志敏等团队合作发现三阴性乳腺癌的潜在治疗新策略

引言癌症干细胞(CSCs)是三阴性乳腺癌(TNBC)细胞中最棘手的亚群，其复发风险高，预后差。然而，根除CSCs仍然很困难。2024年1月29日，复旦大学余科达及邵志敏等团队合作在Cell Reports Medicine (IF 14.3)在线发表题为“Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer”的研究论文，该研究整合了TNBC队列(n = 360)的多组学数据，以确定CSCs的重要标志物，研究发现EMSY，诱导BRCAness表型，优先在乳腺CSCs中表达，促进ALDH+细胞富集，并与不良无复发生存率呈正相关。在机制上，EMSY竞争性地结合对KDM5B酶活性至关重要的Jmjc结构域，重塑蛋氨酸代谢，并以H3K4甲基化依赖的方式促进CSC自我更新和肿瘤发生。此外，EMSY在TNBC细胞中的积累使它们对针对体细胞的PARP抑制剂和针对CSCs的蛋氨酸剥夺敏感。这些发现表明，临床相关的CSCs清除可以通过针对CSCs氨基酸代谢特异性脆弱性的策略来实现。三阴性乳腺癌(TNBC)是一种生物学和临床异质性疾病，约占诊断乳腺癌的12%-17%，由于早期复发率高和治疗选择有限，预后非常糟糕。之前的多组学研究包括465名中国复旦大学上海癌症中心(FUSCC) TNBC患者，描述了一个强大的分类系统，包括四个具有不同分子特征的转录组亚型:间充质样(MES)、腔内雄激素受体(LAR)、免疫调节(IM)和基底样和免疫抑制(BLIS)亚型。进一步揭示了每种转录组亚型的潜在治疗靶点，并对转移性TNBC进行了一项总称试验(FUTURE, ClinicalTrials.gov, NCT03805399)，以评估与这些靶点相关的临床疗效FUTURE试验显示出令人鼓舞的客观缓解率(ORR)为29%，明显高于传统化疗的ORR(5%-15%)。然而，相应的靶向治疗的治疗结果并没有达到预期，特别是对于MES亚型。因此，需要更深入地了解MES子类型以识别新目标。基因表达谱显示，MES亚型在乳腺干细胞通路中富集，并表现出癌症干细胞(CSCs)的特征。CSCs，也被称为乳腺肿瘤启动细胞，是肿瘤细胞的一个亚群，存在于肿瘤块中，具有肿瘤发生、自我更新、耐化疗、复发和转移的特点。因此，特异性消除CSCs可能是最重要的治疗策略之一。自20世纪50年代以来，已有文献证明癌细胞依靠糖酵解而不是氧化磷酸化(OXPHOS)来产生能量，氧化磷酸化是一种更有效的产生ATP的过程。相比之下，最近的一些研究表明，来自多种肿瘤类型(乳腺癌、胶质母细胞瘤、黑色素瘤和胰腺癌)的CSCs依赖于OXPHOS，并且比更成熟的癌细胞具有更低的糖酵解储备。除了对OXPHOS的选择性依赖外，一些研究还记录了CSCs的其他特异性代谢特性。其中包括一些乳腺CSC (BCSC)亚群中脂肪酸β氧化水平升高，乳腺癌中PDK1依赖性代谢重编程，活性氧水平低和谷胱甘肽水平升高，对线粒体翻译和呼吸成分的优先依赖、和特定氨基酸代谢的激活增加。总之，这些数据表明，了解恶性干细胞独特的代谢特性可能是改进CSCs治疗的核心。模式图（Credit: Cell Reports Medicine）EMSY是原癌基因的产物，其位点在乳腺癌和其他人类癌症中经常被扩增。EMSY和CCND1协同工作，促进肺癌和ER阳性他莫昔芬治疗的发病机制。EMSY与BCRA2物理相互作用并抑制BRCA2活性，其过表达诱导BRCAness表型。最新研究表明，EMSY在keap1突变的非小细胞肺癌(NSCLC)中积累可诱导同源重组修复(HRR)缺陷并抑制干扰素反应，从而使其对PARP抑制剂(PARPi)和STING激动剂敏感。此外，EMSY是几个染色质重塑复合体的一部分，并作为干扰素刺激基因的负调节因子。尽管在小鼠异种移植模型中，EMSY在乳腺肿瘤细胞中的过表达促进了肿瘤的生长和转移，但对于EMSY在乳腺CSCs中的功能知之甚少。该研究报道了EMSY介导的蛋氨酸代谢调节的分子基础及其对TNBC肿瘤发生的贡献。值得注意的是，作者提出并实验验证了一种使用奥拉帕尼(一种PARPi)和膳食中蛋氨酸剥夺的组合策略。该研究证明了肿瘤浸润性CSCs中代谢、组蛋白模式和功能谱之间的长期相互作用，这为将这些见解转化为通过靶向其独特的代谢需求来根除耐药CSCs的潜在策略奠定了基础。原文链接https://doi.org/10.1016/j.xcrm.2024.101396责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 颠覆性发现：我们肠道微生物中隐藏的“奇异RNA碎片”

CSCO会议临床研究

2024-01-31

·生物制品圈

Cell子刊 | 复旦大学余科达/邵志敏等团队合作发现三阴性乳腺癌的潜在治疗新策略

摘要癌症干细胞(CSCs)是三阴性乳腺癌(TNBC)细胞中最棘手的亚群，其复发风险高，预后差。然而，根除CSCs仍然很困难。2024年1月29日，复旦大学余科达及邵志敏等团队合作在Cell Reports Medicine 在线发表题为“Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer”的研究论文，该研究整合了TNBC队列(n = 360)的多组学数据，以确定CSCs的重要标志物，研究发现EMSY，诱导BRCAness表型，优先在乳腺CSCs中表达，促进ALDH+细胞富集，并与不良无复发生存率呈正相关。在机制上，EMSY竞争性地结合对KDM5B酶活性至关重要的Jmjc结构域，重塑蛋氨酸代谢，并以H3K4甲基化依赖的方式促进CSC自我更新和肿瘤发生。此外，EMSY在TNBC细胞中的积累使它们对针对体细胞的PARP抑制剂和针对CSCs的蛋氨酸剥夺敏感。这些发现表明，临床相关的CSCs清除可以通过针对CSCs氨基酸代谢特异性脆弱性的策略来实现。三阴性乳腺癌(TNBC)是一种生物学和临床异质性疾病，约占诊断乳腺癌的12%-17%，由于早期复发率高和治疗选择有限，预后非常糟糕。之前的多组学研究包括465名中国复旦大学上海癌症中心(FUSCC) TNBC患者，描述了一个强大的分类系统，包括四个具有不同分子特征的转录组亚型:间充质样(MES)、腔内雄激素受体(LAR)、免疫调节(IM)和基底样和免疫抑制(BLIS)亚型。进一步揭示了每种转录组亚型的潜在治疗靶点，并对转移性TNBC进行了一项总称试验(FUTURE, ClinicalTrials.gov, NCT03805399)，以评估与这些靶点相关的临床疗效FUTURE试验显示出令人鼓舞的客观缓解率(ORR)为29%，明显高于传统化疗的ORR(5%-15%)。然而，相应的靶向治疗的治疗结果并没有达到预期，特别是对于MES亚型。因此，需要更深入地了解MES子类型以识别新目标。基因表达谱显示，MES亚型在乳腺干细胞通路中富集，并表现出癌症干细胞(CSCs)的特征。CSCs，也被称为乳腺肿瘤启动细胞，是肿瘤细胞的一个亚群，存在于肿瘤块中，具有肿瘤发生、自我更新、耐化疗、复发和转移的特点。因此，特异性消除CSCs可能是最重要的治疗策略之一。自20世纪50年代以来，已有文献证明癌细胞依靠糖酵解而不是氧化磷酸化(OXPHOS)来产生能量，氧化磷酸化是一种更有效的产生ATP的过程。相比之下，最近的一些研究表明，来自多种肿瘤类型(乳腺癌、胶质母细胞瘤、黑色素瘤和胰腺癌)的CSCs依赖于OXPHOS，并且比更成熟的癌细胞具有更低的糖酵解储备。除了对OXPHOS的选择性依赖外，一些研究还记录了CSCs的其他特异性代谢特性。其中包括一些乳腺CSC (BCSC)亚群中脂肪酸β氧化水平升高，乳腺癌中PDK1依赖性代谢重编程，活性氧水平低和谷胱甘肽水平升高，对线粒体翻译和呼吸成分的优先依赖、和特定氨基酸代谢的激活增加。总之，这些数据表明，了解恶性干细胞独特的代谢特性可能是改进CSCs治疗的核心。机理模式图（图源自Cell Reports Medicine）EMSY是原癌基因的产物，其位点在乳腺癌和其他人类癌症中经常被扩增。EMSY和CCND1协同工作，促进肺癌和ER阳性他莫昔芬治疗的发病机制。EMSY与BCRA2物理相互作用并抑制BRCA2活性，其过表达诱导BRCAness表型。最新研究表明，EMSY在keap1突变的非小细胞肺癌(NSCLC)中积累可诱导同源重组修复(HRR)缺陷并抑制干扰素反应，从而使其对PARP抑制剂(PARPi)和STING激动剂敏感。此外，EMSY是几个染色质重塑复合体的一部分，并作为干扰素刺激基因的负调节因子。尽管在小鼠异种移植模型中，EMSY在乳腺肿瘤细胞中的过表达促进了肿瘤的生长和转移，但对于EMSY在乳腺CSCs中的功能知之甚少。该研究报道了EMSY介导的蛋氨酸代谢调节的分子基础及其对TNBC肿瘤发生的贡献。值得注意的是，作者提出并实验验证了一种使用奥拉帕尼(一种PARPi)和膳食中蛋氨酸剥夺的组合策略。该研究证明了肿瘤浸润性CSCs中代谢、组蛋白模式和功能谱之间的长期相互作用，这为将这些见解转化为通过靶向其独特的代谢需求来根除耐药CSCs的潜在策略奠定了基础。原文链接：https://doi.org/10.1016/j.xcrm.2024.101396识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

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