更新于：2024-05-01

SHP1

protein tyrosine phosphatase non-receptor type 6

更新于：2024-05-01

基本信息

别名

HCP、HCPH、Hematopoietic cell protein-tyrosine phosphatase

+ [10]

简介

Modulates signaling by tyrosine phosphorylated cell surface receptors such as KIT and the EGF receptor/EGFR. The SH2 regions may interact with other cellular components to modulate its own phosphatase activity against interacting substrates. Together with MTUS1, induces UBE2V2 expression upon angiotensin II stimulation. Plays a key role in hematopoiesis.

关联

项与 SHP1 相关的药物

SC-43

靶点

SHP1

作用机制

SHP1激动剂

在研机构

Rand Biosciences, Inc.

原研机构

SupremeCure Pharma Inc.

在研适应症-

非在研适应症

胆道肿瘤 [+6]

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

SC-60

靶点-

作用机制

SHP1激动剂 [+1]

在研机构

国立台湾大学

原研机构

国立台湾大学

在研适应症

肝细胞癌

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

SC-59

靶点-

作用机制

SHP1激动剂 [+1]

在研机构

国立台湾大学

原研机构

国立台湾大学

在研适应症

肝细胞癌

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 SHP1 相关的临床试验

NCT04733521 / Not yet recruiting临床1/2期

A Phase 1/2, Open-label, Study to Investigate the Safety, Tolerability, and Efficacy of SC-43 Administered in Combination With Cisplatin in Subjects With Advanced or Refractory Non-small Cell Lung Cancer or Biliary Tract Carcinoma

SC-43 is STAT3 inhibitor. Based on the phase I data of SC-43 monotherapy, this is a Phase 1/2, Open-label, Study to Investigate the Safety, Tolerability, and Efficacy of SC-43 Administered in Combination with Cisplatin in Subjects with Advanced or Refractory Non-small Cell Lung Cancer or Biliary Tract Carcinoma

开始日期2021-05-01

申办/合作机构

Rand Biosciences, Inc.

NCT03443622 / Withdrawn临床1期

Phase I Open-Label Dose-Escalating Study to Determine the Safety, Tolerability, Maximum Tolerated Dose, and Pharmacokinetics of SC-43 Oral Solution in Subjects With Refractory Solid Tumors

This phase I study will be conducted in an open-label, conventional 3+3 dose escalation design manner (for the first 28 days of dosing) followed by an extension period for subjects responsive to the study drug to continue dosing up to 52 weeks. This study is intended to assess the safety and efficacy of the investigational product (IP), SC-43 Oral Solution, in subjects with refractory solid tumors. Subjects who have diseases progressing unresponsive to the previous treatments or who have no standard treatments for their current diseases will be enrolled in this study once the eligibility is confirmed.
During the first 28 days, the study will be done in the conventional 3+3 design to determine the maximum tolerated dose (MTD) of SC-43 Oral Solution. The dose will be increased in a step-wise fashion from the initial dose of 100 mg/day to the dose of 200, 400, 600, 900, and 1200 mg/day. The pharmacokinetics (PK) of SC-43 will also be measured in this period.
The dose of SC-43 Oral Solution will be escalated to the subsequent cohorts when there is no dose-limiting toxicity (DLT) in 3 subjects or only one DLT in 6 subjects of the previous cohort, and it is recommended by Data and Safety Monitoring Board (DSMB). The safety results will be reviewed by DSMB after the last subject in the each cohort has finished the Visit 6 (Day 29), and DSMB will determine if it is safe to proceed to the next dose cohort.
Subjects who have finished the 28-day dose escalation period and with complete response (CR), partial response (PR), or stable disease (SD) will be eligible to enter the extension period and continue SC-43 Oral Solution therapy up to 52 weeks or until occurrence of unacceptable toxicity, withdrawn consent, disease progression, not receiving medical benefit as considered by investigators, loss of follow-up, or death, whichever comes first. For ethical and safety concerns, the dosage used in this extension period can be adjusted and different from the original dosage assignment. The actual dose of SC-43 Oral Solution, which must be confirmed safe, administered during this extension period will be at the investigator's discretion.

开始日期2021-05-01

申办/合作机构

SupremeCure Pharma Inc.

100 项与 SHP1 相关的临床结果

登录后查看更多信息

100 项与 SHP1 相关的转化医学

登录后查看更多信息

0 项与 SHP1 相关的专利（医药）

登录后查看更多信息

2,281

项与 SHP1 相关的文献（医药）

2024-02-24·Cancer immunology, immunotherapy : CII

Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells.

Article

作者: Narendiran Rajasekaran ; Xiaoguang Wang ; Sruthi Ravindranathan ; Daniel J Chin ; Su-Yi Tseng ; Scott L Klakamp ; Kate Widmann ; Varun N Kapoor ; Vladimir Vexler ; Patricia Keegan ; Sheng Yao ; Theresa LaVallee ; Sanjay D Khare

Over the past decade, US Food and Drug Administration (FDA)-approved immune checkpoint inhibitors that target programmed death-1 (PD-1) have demonstrated significant clinical benefit particularly in patients with PD-L1 expressing tumors. Toripalimab is a humanized anti-PD-1 antibody, approved by FDA for first-line treatment of nasopharyngeal carcinoma in combination with chemotherapy. In a post hoc analysis of phase 3 studies, toripalimab in combination with chemotherapy improved overall survival irrespective of PD-L1 status in nasopharyngeal carcinoma (JUPITER-02), advanced non-small cell lung cancer (CHOICE-01) and advanced esophageal squamous cell carcinoma (JUPITER-06). On further characterization, we determined that toripalimab is molecularly and functionally differentiated from pembrolizumab, an anti-PD-1 mAb approved previously for treating a wide spectrum of tumors. Toripalimab, which binds the FG loop of PD-1, has 12-fold higher binding affinity to PD-1 than pembrolizumab and promotes significantly more Th1- and myeloid-derived inflammatory cytokine responses in healthy human PBMCs in vitro. In an ex vivo system employing dissociated tumor cells from treatment naïve non-small cell lung cancer patients, toripalimab induced several unique genes in IFN-γ and immune cell pathways, showed different kinetics of activation and significantly enhanced IFN-γ signature. Additionally, binding of toripalimab to PD-1 induced lower levels of SHP1 and SHP2 recruitment, the negative regulators of T cell activation, in Jurkat T cells ectopically expressing PD-1. Taken together, these data demonstrate that toripalimab is a potent anti-PD-1 antibody with high affinity PD-1 binding, strong functional attributes and demonstrated clinical activity that encourage its continued clinical investigation in several types of cancer.

2024-02-23·Nature cell biology

Metabolic regulation of chemoresistance and immuno-surveillance in AML by SHP-1.

Article

The chemoresistant and immunoevasive characteristics of leukemia stem cells (LSCs) impede the treatment efficacy for acute myeloid leukemia (AML). We find that inhibiting the tyrosine phosphatase SHP-1 effectively alters the metabolic state of LSCs, making them more susceptible to chemotherapy and immune surveillance in AML.

2024-02-22·Molecular cell

Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.

Article

作者: Hao Li ; Zhejian Ji ; Joao A Paulo ; Steven P Gygi ; Tom A Rapoport

Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex rather than substrate recruitment. Experiments in yeast cells confirm that many proteins undergo bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase before being degraded.

项与 SHP1 相关的新闻（医药）

2024-02-04

·生物制药小编

代谢调控T细胞活化结果

T细胞活化主要包括三段信号：第一信号TCR-MHC、第二信号共刺激和第三信号细胞因子信号转导。大量的证据表明，T细胞的反应在很大程度上依赖于代谢产物的可及性。并且代谢物会通过营养感知和其他机制传递自己的信号。代谢在T细胞活化中的作用：①代谢物不仅是T细胞活化每一个阶段中的基本媒介，而且还提供各自的离散信号来控制T细胞的激活。②代谢物并不只是简单地传播核心T细胞信号，而是将它们自己的偏向传递给CD4+和CD8+ T细胞反应的功能结果。代谢物与T细胞免疫的相互作用不是中性的，某些代谢物的功能偏向决定了T细胞的激活。Nat Immunol.（一）代谢调节TCR信号氨基酸的可获得性会调节TCR的激活和免疫突触的形成。例如：细胞外天冬酰胺水平的增加提高了CD8+T细胞的激活初期和抗肿瘤细胞的效应功能。激活的T细胞对精氨酸的摄取比初始T细胞高得多，细胞内的精氨酸储存在T细胞激活后迅速代谢，从而影响T细胞存活和抗肿瘤功能。T细胞激活过程中会通过Myc20依赖而增加对谷氨酰胺的摄取。在中心，近端抗原特异性信号则被天冬酰胺增强，天冬酰胺促进LCK活性，而镁离子帮助LFA-1进入其活性构象，从而促进与靶细胞更强的附着。不过T细胞在激活过程中对氨基酸的代谢需求通常是时间依赖性的。此外，ROS可降低SHP1的活化，从而促进近端TCR信号强度。肌动蛋白细胞骨架重排则受到溶血磷脂酸和GML等几种代谢物的影响。金属离子代谢：无镁条件下活化的CD8+T细胞代谢流和细胞因子释放较差。镁与LFA-1的两个亚基上的金属离子依赖的黏附部位结合，促进其活跃的“延伸”构象，从而使CD8+T细胞能够完全激活.锌内流在TCR信号转导和激活中也起着关键作用。TCR结扎后增加的锌内流减少了磷酸酶SHP1对TCR激活复合体的募集，并增加了ZAP70的磷酸化。代谢物钙离子同时还是TCR信号的特征之一，在TCR信号框架中是一个重要的离散信号。钙流是许多与T细胞激活相关的代谢变化的关键，可以诱导糖酵解和氧化磷酸化，并反过来受到代谢物的影响。不同的代谢产物对钙的流动有不同的调节作用，例如醋酸盐隔离钙流动，而维生素D促进钙流动。同一样代谢物的具体作用效果也受到细胞环境和暴露剂量的影响。例如，短链脂肪酸醋酸酯可以在TME中促进肿瘤浸润性淋巴细胞的效应功能，还能促进CD8+ T细胞的糖酵解，发挥免疫功能。但同时，暴露于高浓度的醋酸盐则会抑制钙离子流动，从而抑制CD8+ T细胞糖酵解。（二）代谢通过PI3K-AKT-mTOR通路调节共刺激信号。代谢物反馈并调节PI3K途径，PI3K途径激活会启动下游一系列信号，包括丝氨酸/苏氨酸激酶AKT的激活、NFAT核定位和mTOR激酶活性激活。每种代谢物则会向下游信号施加其独特的偏向，以影响T细胞的反应。PI3K-AKT糖酵解代谢过程在TCR激活后迅速上调促进PI3K活性，而磷脂酸和NAC促进AKT激活，从而进一步放大PI3K-AKT-mTOR信号通路。PI3K信号驱动维持强PI3K信号所需的代谢燃料的激活。甲氧丙戊酸代谢和丁酸则通过驱动mTORC1活性，提高T细胞初始激活时的翻译活性。维A酸(retinoic acid，RA)通过AKT信号和mTOR激活实现对CD4+ T细胞的激活作用。由于RA与RARα结合促进RARα的核定位，高浓度RA有利于RA介导的由核RARα介导的Treg细胞分化，而低浓度RA则通过T细胞代谢和Th17细胞介导的炎症反应促进高PI3K-AKT信号的表达。同时，LDHA缺乏的CD8+T细胞通过糖酵解产生的ATP减少，选择性地削弱PI3K依赖的信号，而使近端TCR信号不受影响。作为正反馈回路的一部分，AKT信号调节葡萄糖摄取。静息T细胞中AKT的结构性激活增加了葡萄糖摄取，但与CD28刺激的细胞中的葡萄糖摄取水平不匹配。磷脂酶D-1(PLD1)也促进T细胞激活过程中的AKT激活。mTORmTOR在PI3K-AKT信号下游被激活，但也受到许多代谢物的直接调节。鉴于mTOR是T细胞激活开始时的一个关键代谢开关，T细胞对外部来源代谢物对mTOR活性的调节高度敏感。因此，许多代谢物，包括氨基酸、脂肪酸和金属离子，都是改变T细胞代谢的离散信号。大多数改变T细胞命运的代谢物特异性信号很可能在mTOR途径内汇聚。氨基酸感应：在CD8+T细胞中，氨基酸缺乏会迅速削弱mTOR活性。缺乏ASCT2的CD4+T细胞对谷氨酰胺和亮氨酸的摄取减少，从而抑制mTORC1的激活，这可以通过摄入过量的谷氨酰胺或亮氨酸来弥补。氨基酸转运体LAT1介导细胞对组氨酸、苯丙氨酸和色氨酸等大的中性氨基酸的摄取，是维持CD8+T细胞mTORC1活性的关键。在肿瘤中，与细胞坏死相关的高水平的钾会削弱AKT-mTOR的磷酸化，并在体外和体内抑制CD8+T细胞的反应。钾通道Kv1.3在CD8+T细胞中的过表达增强了它们在肿瘤中的功能，并促进了B16黑色素瘤的清除。mTOR信号还受到脂质衍生的翻译后修饰以及丁酸盐等单链脂肪酸的可及性的影响。依赖Fntb的蛋白质预烯基化在Treg细胞激活期间维持mTORC1的活性。在翻译后修饰之外，用SCFA丁酸盐处理CD4+T细胞可促进mTOR激活。参考文献：1.Wilfahrt, D., Delgoffe, G.M. Metabolic waypoints during T cell differentiation. Nat Immunol (2024). https://doi.org/10.1038/s41590-023-01733-52.Ginefra, P., Hope, H. C., Spagna, M., Zecchillo, A. & Vannini, N. Ionic regulation of T-cell function and anti-tumour immunity. Int. J. Mol. Sci. 22, 13668 (2021).

2024-01-24

·生物谷

复旦大学生物医学研究院许杰团队报道Galectin-8通过结合LILRB4诱导肿瘤微环境中M-MDSC的作用

髓系来源抑制细胞（MDSC）在肿瘤免疫微环境中发挥关键作用，但由于缺乏特异性靶点，针对其的靶向药物开发面临挑战。LILRB4是一种含有ITIM结构域的免疫检查点受体，与MDSC介导的肿瘤免疫抑制有关。尽管针对LILRB4的药物在临床前和临床研究中有所进展，但治疗效果并不理想。目前尚不清楚与肿瘤微环境中的MDSC相关的LILRB4功能性配体，这阻碍了阻断性抗体的开发和伴随诊断。近日，复旦大学生物医学研究院许杰课题组在Cell Reports Medicine杂志上发表了题为“Discovery of Galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors”的文章，该研究首次报道了Galectin-8作为LILRB4的肿瘤相关功能性配体，通过下游的STAT3和NF-κB通路来诱导M-MDSC，从而促进免疫抑制和肿瘤的生长，并研发了具有阻断功能的治疗抗体，证明了阻断Galectin-8与LILRB4的抗体能够减缓多种高表达Galectin-8的肿瘤在小鼠体内的生长，具有潜在治疗和转化价值。原文链接：https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00603-1研究人员发现Galectin-8具有独特的表达模式，并对肿瘤预后和免疫浸润因子产生影响。Galectin-8与MDSC具有相关性，进一步的研究显示Galectin-8与LILRB4以高亲和力结合，调控胞内的SHP-1-STAT3/NF-κB通路。Galectin-8能够诱导M-MDSC的增加并抑制T细胞增殖。利用基因敲除小鼠模型，研究人员证明了LILRB4 的存在和Galectin-8的过表达功能促进小鼠M-MDSC的增加和肿瘤生长。通过分别开发了抗LILRB4抗体和抗Galectin-8抗体，研究者证明了双向阻断均能够抑制Galectin-8和LILRB4作用带来的效果，并且研究者对抗体的表位进行了分析，特别对于阻断性抗体与LILRB4的结合表位进行了明确定位（下图B-C）。随后，利用人源化小鼠肿瘤模型，研究者证明抗体抑制表达Galectin-8肿瘤的生长（下图K-L）。这一研究发现了LILRB4的新功能性配体Galectin-8，揭示了配体受体互作在M-MDSC诱导和肿瘤免疫抑制微环境塑造中的重要作用；探究了参与M-MDSC诱导的下游信号通路。同时，本研究开发了具有阻断功能的治疗性抗体，显示了功能性配体的发现为抗体药物的早起筛选开发提供重要依据，并提供Galectin-8的表达水平作为抗体治疗的筛选标准，具有潜在转化价值。复旦大学生物医学研究院研究员许杰为本论文通讯作者，博士生王一婷为论文的第一作者。原文链接：https://shmc.fudan.edu.cn/news/2024/0118/c1892a139093/page.htm本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床研究

2024-01-14

·生物谷

Nature子刊 | 范高峰和王皞鹏课题组揭示T细胞发育调控基因THEMIS作用机制

1月4日，上海科技大学生命科学与技术学院范高峰/王皞鹏课题组在Nature Structural & Molecular Biology上发表题为“THEMIS is a substrate and allosteric activator of SHP1, playing dual roles during T cell development”的研究论文，揭示T细胞发育调控基因THEMIS的具体作用机制，解决了该领域长期以来的争论。T细胞是获得性免疫系统中主要的功能执行者，负责识别抗原并做出免疫应答，而胸腺是T细胞发育和分化的场所。T细胞发育受到胸腺微环境和信号转导控制，这些过程在多个水平上受到精确的时空调控，其中酪氨酸磷酸化在T细胞信号级联中的调控尤为重要。为了揭示酪氨酸磷酸酶在T细胞中的底物谱图，本研究结合邻近标记技术PUP-IT和酪氨酸磷酸酶底物捕获突变体机制，开发了新技术PEPSI (PUP-IT Enhanced PTP Substrate Identification)用于高通量鉴定磷酸酶作用底物。研究人员通过PEPSI技术在T淋巴细胞中开展酪氨酸磷酸酶SHP1的底物鉴定，发现了SHP1的新型底物THEMIS，证实了THEMIS Y34位点的磷酸化修饰由LCK和SHP1进行正反调控。为揭示THEMIS磷酸化的生物学意义，本研究构建了THEMIS Y34F敲入和THEMIS敲除小鼠，通过流式细胞术分析小鼠T细胞发育和增殖情况，发现与THEMIS敲除小鼠的表型类似，THEMIS Y34F敲入小鼠胸腺T细胞从CD4和CD8双阳性阶段发育到CD4单阳性阶段有明显的阻滞，并且脾脏中的CD4单阳性T细胞明显减少。本研究还发现磷酸化的THEMIS可以激活SHP1，这提示THEMIS可能是SHP1的一个变构底物。进一步利用氢氘交换质谱、表面等离子共振等技术，发现磷酸化的THEMIS肽段结合SHP1的PTP结构域K520位点从而稳定SHP1的激活构象。图1. THEMIS Y34调控的CD4 T细胞发育本研究提出了新的THEMIS作用模型：在TCR刺激后，LCK磷酸化THEMIS的Y34位点，磷酸化的THEMIS将SHP1稳定在开放的构象，激活的SHP1会抑制TCR信号的传递，从而保证正常的阳性选择。该成果不仅揭示了调控T细胞发育的新机制和磷酸酶SHP1活性调控的新机制，并为研究TCR信号通路调控的机制和发掘潜在的T细胞治疗靶点提供了新思路。图2. THEMIS的作用模型上海科技大学生命学院常任副教授范高峰和常任副教授王皞鹏为论文的共同通讯作者，博士后张佳丽、博士研究生江振洲为论文的共同第一作者。上海科技大学生命学院常任正教授Tiffany Horng，常任副教授庄敏，助理教授张力烨，生命学院组学分析平台主任郝丕良，免疫化学所研究员白芳，中国农业科学院深圳农业基因组研究所研究员左二伟，中国科学院上海药物所研究员郑杰提供了大力支持。文章链接：https://www.nature.com/articles/s41594-023-01131-3本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

细胞疗法