预约演示

更新于：2025-05-07

ABL2

更新于：2025-05-07

基本信息

别名

Abelson murine leukemia viral oncogene homolog 2、Abelson tyrosine-protein kinase 2、Abelson-related gene

+ [10]

简介

Non-receptor tyrosine-protein kinase that plays an ABL1-overlapping role in key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion and receptor endocytosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like MYH10 (involved in movement); CTTN (involved in signaling); or TUBA1 and TUBB (microtubule subunits). Binds directly F-actin and regulates actin cytoskeletal structure through its F-actin-bundling activity. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as CRK, CRKL, DOK1 or ARHGAP35. Adhesion-dependent phosphorylation of ARHGAP35 promotes its association with RASA1, resulting in recruitment of ARHGAP35 to the cell periphery where it inhibits RHO. Phosphorylates multiple receptor tyrosine kinases like PDGFRB and other substrates which are involved in endocytosis regulation such as RIN1. In brain, may regulate neurotransmission by phosphorylating proteins at the synapse. ABL2 acts also as a regulator of multiple pathological signaling cascades during infection. Pathogens can highjack ABL2 kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, ABI1. Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity).

关联

项与 ABL2 相关的药物

EP4410779

专利挖掘

靶点

ABL1 x ABL2 x BCR

作用机制

Tyrosine kinase inhibitors

在研机构

江苏豪森药业集团有限公司

原研机构

江苏豪森药业集团有限公司

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

CN116135851

专利挖掘

靶点

ABL1 x ABL2 x BCR x Bcr-Abl

作用机制

ABL1抑制剂 [+1]

在研机构

Wuhan Zhongcheng Kangjian Biomedical Technology Co., Ltd.

原研机构

Wuhan Zhongcheng Kangjian Biomedical Technology Co., Ltd.

在研适应症

自身免疫性疾病 [+5]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

DB-3-291

靶点

ABL2 x BLK x CSK x WEE1

作用机制

ABL2 antagonists [+3]

在研机构-

原研机构

Dana-Farber Cancer Institute, Inc. [+1]

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ABL2 相关的临床结果

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100 项与 ABL2 相关的转化医学

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0 项与 ABL2 相关的专利（医药）

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270

项与 ABL2 相关的文献（医药）

2025-03-01·Molecular and Cellular Biochemistry

The BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling

Article

作者: Zibrova, Darya ; Ernst, Thomas ; Hochhaus, Andreas ; Heller, Regine

AbstractBCR::ABL1 inhibitors, the treatment of choice for the majority of patients with chronic myeloid leukaemia (CML), can cause vascular side effects that vary between agents. The exact underlying mechanisms are still poorly understood, but the vascular endothelium has been proposed as a site of origin. The present study investigates the effects of three BCR::ABL1 inhibitors, ponatinib, nilotinib and imatinib, on angiogenesis and signalling in human endothelial cells in response to vascular endothelial growth factor (VEGF). The experiments were performed in endothelial cells isolated from human umbilical veins. After exposure to imatinib, ponatinib and nilotinib, the angiogenic capacity of endothelial cells was assessed in spheroid assays. VEGF-induced signalling pathways were examined in Western blotting experiments using different specific antibodies. RNAi technology was used to downregulate proteins of interest. Intracellular cGMP levels were measured by ELISA. Imatinib had no effect on endothelial function. Ponatinib inhibited VEGF-induced sprouting, while nilotinib increased spontaneous and VEGF-stimulated angiogenesis. These effects did not involve wild-type ABL1 or ABL2, as siRNA-mediated knockdown of these kinases did not affect angiogenesis and VEGF signalling. Consistent with their effects on sprouting, ponatinib and nilotinib affected angiogenic pathways in opposite directions. While ponatinib inhibited VEGF-induced signalling and cGMP formation, nilotinib activated angiogenic signalling, in particular phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2). The latter occurred in an epidermal growth factor receptor (EGFR)-dependent manner possibly via suppressing Fyn-related kinase (FRK), a negative regulator of EGFR signalling. Both, pharmacological inhibition of Erk1/2 or EGFR suppressed nilotinib-induced angiogenic sprouting. These results support the notion that the vascular endothelium is a site of action of BCR::ABL1 inhibitors from which side effects may arise, and that the different vascular toxicity profiles of BCR::ABL1 inhibitors may be due to their different actions at the molecular level. In addition, the as yet unknown pro-angiogenic effect of nilotinib should be considered in the treatment of patients with comorbidities associated with pathological angiogenesis, such as ocular disease, arthritis or obesity.

2025-03-01·The Journal of Thoracic and Cardiovascular Surgery

Extracellular vesicles in lung donor plasma: Potential indicators of donor organ quality

Article

作者: Nykänen, Antti I ; Puhka, Maija ; Helanterä, Ilkka ; Lemström, Karl B ; Dellgren, Göran ; Laitinen, Saara ; Joo, SeoJeong ; Syrjälä, Simo O ; Holmberg, Erik C ; Åberg, Fredrik ; Dhaygude, Kishor ; Magnusson, Jesper ; Lund, Thomas Kromann ; Leuckfeld, Inga ; Holmström, Emil ; Krebs, Rainer ; Raivio, Peter ; Svahn, Johan

OBJECTIVEBrain death induces systemic inflammation and hemodynamic changes that can lead to lung injury, impacting the quality of donor organs for transplantation. Extracellular vesicles (EVs) are cell-derived nanoparticles that carry functional biomolecules and reflect the physiological state of their cells of origin. We hypothesized that EVs from brain-dead donors may indicate lung injury and may be used to predict primary graft dysfunction (PGD) in lung transplant recipients.METHODSWe performed transcriptomic profiling of plasma EVs from 44 brain-dead lung donors and 9 healthy controls using next-generation sequencing. Differential gene expression was assessed, followed by pathway enrichment analyses. The results were validated by quantitative polymerase chain reaction using the study cohort and an independent cohort. Variable importance of projection score analysis and regression models were used to identify EV transcripts associated with PGD in recipients.RESULTSTranscriptomic analysis revealed that 13% of protein-coding genes were differentially expressed in lung donor EVs compared with controls, with 92% of these genes upregulated. Upregulated genes were enriched in pathways related to inflammation, coagulation, tissue remodeling, and metabolism. Seven key EV transcripts, RAD51D, ABL2, FGFR1, WDR82, PTBP3, OPRL1, and XG were identified as potential PGD indicator. These transcripts were associated with processes such as DNA damage repair, signal transduction, and inflammation, which may contribute to posttransplant lung injury.CONCLUSIONSDonor plasma EVs carry distinct transcriptomic signatures associated with injury and inflammation. Specific EV transcripts, such as RAD51D and XG, hold promise as independent predictive biomarkers for PGD, possibly providing new tools for evaluating donor organ quality and improving lung transplant outcomes.

2025-01-01·BMJ Case Reports

Cryptic to conventional cytogenetics: Philadelphia-like ALL presenting with hypereosinophilia

Article

作者: Yenwong Fai, Leonard ; Wei, Sainan ; Chahine, Zena ; Qasrawi, Ayman

BCR::ABL1-like B-lymphoblastic leukaemia (B-ALL) neoplasms lack the BCR::ABL1 translocation but have a gene expression profile like BCR::ABL1 positive B-ALL. This includes alterations in cytokine receptors and signalling genes, such asCRLF2, ABL1, ABL2, JAK2, PDGFRBandEPOR. Cases with CRLF2 rearrangements account for approximately 50% of cases of Philadelphia-like acute lymphoblastic leukaemia (Ph-like ALL), and the frequency of specific genomic lesions varies with ethnicity such that IGH::CRLF2 translocations are more common in Hispanics and Native Americans.We report two cases of BCR::ABL1-like ALL, with significant eosinophilia. A Hispanic man in his early 20s and a Hispanic woman in her 50s presented with leukocytosis and eosinophilia. Bone marrow flow cytometry revealed lymphoblasts expressing CD19, CD10, partial CD20, CD22, CD79a, CD38, CD34, TdT and HLA-DR. Examination of the bone marrow biopsy and aspirate exhibited a hypercellular bone marrow with increased blasts and elevated eosinophils. Fluorescence in situ hybridisation (FISH) demonstrated a cryptic chromosomal rearrangement between the X chromosome and chromosome 14 at breakpoints involving IGH at 14q32 and CRLF2 at Xp22.33, t(X;14)(p22.33; q32).These findings confirmed the diagnosis of BCR::ABL1-like B-ALL with IGH::CRLF2 rearrangement. One patient (man) attained complete remission with induction therapy using the paediatric CALGB 10403 protocol, while the other patient (woman) had a poor outcome after receiving a hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone regimen. These two cases demonstrate an unusual presentation of BCR::ABL1-like B-ALL and emphasise the importance of appropriate cytogenetic studies for correct diagnosis. When treated with conventional chemotherapy, these cases carry a poor prognosis and might require allogeneic transplantation.

项与 ABL2 相关的新闻（医药）

2023-11-26

·生物探索

破解数十年难题！福建农林大学最新Cell

生长素是一种重要的植物激素，其细胞外感知已经争论了几十年。生长素结合蛋白1(ABP1)与典型跨膜激酶(TMKs)相互作用，并被认为是细胞外生长素受体，但由于ABP1敲除突变体缺乏明显的形态表型，其作用存在争议。2023年11月17日，福建农林大学徐通达及杨贞标共同通讯（于永强、唐文鑫、林文伟、周翔及李围为论文共同第一作者）在Cell在线发表题为“ABLs and TMKs are co-receptors for extracellular auxin”的研究论文，该研究发现了两个新的生长素结合蛋白ABL1和ABL2，它们定位于外质体，并以生长素依赖的方式直接与TMKs的细胞外结构域相互作用。功能冗余的ABL1和ABL2在遗传上与TMK相互作用，并表现出与ABP1重叠的功能，同时独立于ABP1。重要的是，TMK1本身的胞外结构域与生长素结合，并在生长素结合中与ABP1或ABL1协同作用。因此，该研究发现生长素受体ABL1和ABL2与ABP1具有重叠但不同的功能，并与TMKs一起作为细胞外生长素的共受体。生长素几乎调节植物生长、发育和对环境的反应的各个方面，并已被证明可以控制发生在几秒钟内的转录无关的快速反应以及较慢的转录反应。后者需要细胞内受体转运抑制剂应答1(TIR1)/生长素信号传导F-BOX蛋白(AFBs)促进其共受体生长素/吲哚-3-乙酸(AUX/IAA)转录抑制因子的降解，并作为腺苷酸环化酶。越来越多的研究表明，生长素诱导的许多效应，如质膜超极化、细胞质Ca2+瞬态、植物(ROP)GTP酶的RHO激活、纤维肉瘤(RAF)样激酶依赖性细胞质流的快速加速和原生质体肿胀，都过于迅速，无法依赖于转录调节。大多数这些快速生长素反应明显受到一类生长素受体的调节，这些受体不同于核TIR1/AFB受体，并且可能定位于细胞表面。生长素作用的一个关键标志是生长素在邻近细胞的质膜和细胞壁上的动态通量，以及其在组织和器官上的长距离流动，这种流动依赖于细胞间的通量。因此，必须严格监测和控制细胞外增殖生长素水平。此外，当细胞外生长素水平发生变化时，需要细胞表面生长素信号传导来快速调节细胞质反应。事实上，跨膜激酶(TMK)家族受体样激酶是许多生长素反应所必需的质膜定位生长素信号传导成分，包括细胞壁酸化、ROP GTPase激活和蛋白质磷酸化等快速反应。生长素激活TMK磷酸化，激活的TMK结构域可直接磷酸化吲哚-3-乙酸诱导32/34(IAA32/34)、自抑制H+-ATP酶异构体(AHA)、丝裂原活化蛋白激酶激酶4/5-丝裂原活化蛋白激酶3/6 (MKK4/5-MPK3/6)、拟南芥色氨酸氨基转移酶1(TAA1)、脱落酸不敏感1/2 (ABI1/2)等一系列效应物，调控多种发育过程然而，激活TMK依赖性生长素反应的生长素信号感知的分子机制仍然是谜。文章模式图（图源自Cell）生长素结合蛋白1(ABP1)以生长素依赖的方式与TMK1细胞外结构域形成复合物，表明它可能感知生长素激活TMK依赖的生长素反应。然而，ABP1在生长素感知/信号传导中的作用一直存在争议，因为在拟南芥中敲除单拷贝ABP1基因并没有产生可见的表型。相比之下，敲除所有四个功能冗余的tmk，如tmk1;tmk2;tmk3;tmk4突变体，可诱导广泛的表型，包括拟南芥的胚胎和幼苗致死。最近的一项研究表明，在拟南芥中，abp1和tmk1无突变体在生长素诱导的快速全局磷酸化反应方面表现出类似的缺陷，并且这些生长素反应需要与abp1结合，这证实了ABP1在TMK1依赖性生长素感知/信号传导中的作用。然而，这项研究未能解释为什么许多依赖TMK的发育过程和生长素反应在abp1无突变体中不受影响。重要的是，典型的TMK是否以及如何感知细胞外生长素仍未得到解决。鉴于abp1敲除突变体缺乏明显的表型，且abp1主要定位于内质网(ER)，研究人员推测存在其他细胞外ABPs，可能与TMKs一起作用，感知细胞外生长素。为了寻找这些蛋白，该研究对拟南芥pTMK1::TMK1-FLAG(TMK1-FLAG)进行了免疫沉淀-质谱(IP-MS)分析，并鉴定出两种高度相关的发芽样蛋白(GLPs)，它们含有生长素结合盒状基序，类似于ABP1中发现的A-box。该研究证明了这些ABP1样(ABL)蛋白和TMKs作为感知细胞外生长素的共受体。参考文献：Yu Y, Tang W, Lin W, Li W, Zhou X, et al.ABLs and TMKs are co-receptors for extracellular auxin. Cell .2023 Nov 14:S0092-8674(23)01134-0.doi: 10.1016/j.cell.2023.10.017. Epub ahead of print. PMID: 37979582.文章来源：“iNature”责编|探索君排版|探索君End往期精选围观科学家称，每25人中就有1人携带“短寿”基因热文表观遗传变化在癌症进展中至关重要热文新型柔性X射线探测器有望彻底改变癌症治疗热文最新发现：人类毛囊具备触觉感知能力热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

AHA会议临床结果

2022-09-06

·生物谷

Cell Rep：一种白血病药物或有望潜在治疗转移性HER2阳性的乳腺癌

来自杜克大学医学院等机构的科学家们通过研究发现，一种治疗白血病的药物或能成功阻断HER2阳性的乳腺癌肿瘤在患者大脑中定植。人类表皮生长因子受体2阳性（HER2+/ERBB2）的乳腺癌患者经常会发生癌细胞脑转移，而HER2靶向性疗法在治疗脑转移癌症方面并不成功，部分是因为患者机体血脑屏障渗透性较差以及癌细胞耐受性的出现。近日，一篇发表在国际杂志Cell Reports上题为“ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain”的研究报告中，来自杜克大学医学院等机构的科学家们通过研究发现，一种治疗白血病的药物或能成功阻断HER2阳性的乳腺癌肿瘤在患者大脑中定植。这一研究结果或为科学家们进行人类临床试验提供了一定的证据，研究人员提出了一种潜在的新型策略来破坏乳腺癌转变为致命性癌症的主要途径之一。Ann Marie Pendergast教授说道，如今我们在治疗HER2阳性乳腺癌患者上取得了巨大的进展，但当肿瘤逃脱疗法治疗时，其通常就会转移到患者大脑中。当癌症的大脑转移开始时，治疗或许就不会那么成功了，因为肿瘤已经产生了耐药性，或者疗法并不能有效渗透血脑屏障，这对于患者而言仍然是一种毁灭性的疾病诊断。这项研究中，研究人员分析了HER2是如何促进乳腺癌生长的，尤其是在对延长患者生命上非常成功的靶向性疗法产生耐受性后，HER2蛋白是30%的乳腺癌发生的驱动力，其中大约有45%的患者会发生脑转移。研究人员重点对一对名为ABL1和ABL2的特殊激酶进行研究，这两种激酶能调节HER2的表达，于是研究者通过研究发现，这些激酶在创造促进HER2在乳腺癌细胞表面积累并促进乳腺癌肿瘤转移的条件上扮演着重要角色。一种白血病药物或有望潜在治疗转移性HER2阳性的乳腺癌。图片来源：Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111268 通过对小鼠进行实验后，研究者发现，他们或许能利用名为asciminib的白血病药物来阻断ABL激酶的功能，作为一种激酶抑制，这种药物在携带肿瘤的小鼠体内并不会受到血脑屏障的阻挡，并能成功干预ABL激酶的信号机制。通过阻断ABL的信号网络，这种疗法或许就能让HER2蛋白无法在乳腺癌细胞中积累，并能关闭促进乳腺癌细胞增殖和扩散的过程。研究者Pendergast表示，这些研究发现支持科学家们利用ABL激酶抑制剂来帮助治疗HER2阳性的癌症脑转移。综上，本文研究结果支持ABL激酶能通过YB结合蛋白1在脑转移靶点的转化调节过程中或许扮演着重要角色，并能为HER2+脑转移患者提供一种新型的治疗性靶点。（生物谷Bioon.com）原始出处： Courtney M. McKernan，Aaditya Khatri，Molly Hannigan, et al. ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111268

2022-08-24

·PRNewswire

Inhibikase Therapeutics Announces Dosing of First Patient in its Phase 2a '201' Clinical Trial of IkT-148009 to Treat Parkinson's Disease

BOSTON and ATLANTA, Aug. 23, 2022 /PRNewswire/ -- Inhibikase Therapeutics, Inc. (Nasdaq: IKT) (Inhibikase), a clinical-stage pharmaceutical company developing therapeutics to modify the course of Parkinson's disease and related disorders, today announced dosing of the first patient in its Phase 2a study ('201 trial') evaluating IkT-148009, the Company's novel Abelson Tyrosine Kinase, or c-Abl, inhibitor for the treatment of Parkinson's disease. "Dosing of the first patient in our Phase 2a '201' trial represents a major milestone in the development of IkT-148009 for the treatment of Parkinson's disease and related disorders," commented Milton H. Werner, Ph.D., President and Chief Executive Officer. "Parkinson's disease remains one of the most prevalent neurodegenerative disorders and affects nearly one million people in the U.S. annually. Our research continues to validate the critical role that c-Abl, a mechanistically defined target, plays in the initiation and progression of Parkinson's disease, as well as the potential of IkT-148009 as a promising new approach to disease modification. Preclinical data in animal models of human PD suggested that functional recovery could be achieved in less than 8 weeks in animal." "We are excited to evaluate the safety and tolerability of IkT-148009 in a three-month dosing regimen, which may also have the potential to show preliminary benefits from IkT-148009 inhibition of c-Abl in patients. 12 of up to 40 planned sites have been opened, and as the summer vacation months pass, we anticipate seeing an uptick in screening rates and enrolling patients in this study as we seek to deliver on our mission to improve the lives of patients suffering from devastating neurodegenerative diseases," concluded Dr. Werner. The 201 trial is a 1:1:1:1 randomized, double-blind, twelve-week dosing trial that will measure the safety, tolerability and steady-state pharmacokinetics of IkT-148009 as primary endpoints. The trial will enroll approximately 120 patients with untreated Parkinson's disease (Hoehn & Yahr North America with additional site activations ongoing on a rolling basis. For more information regarding the trial design please see www.clinicaltrials.gov (identifier: NCT05424276). About IkT-148009 IkT-148009 is a selective c-Abl kinase inhibitor that uniquely inhibits c-Abl and the closely related Abl2/Arg enzyme without inhibition of other members of the Abl-kinase family, namely c-Kit or PDGFRa/b. It has nearly 25x the potency of the anticancer agent Imatinib against wild type c-Abl in enzyme inhibition assays. IkT-148009 has been designed to have a predictable low toxicity profile with the ability to cross the blood brain barrier and accumulate in the brain, features that were validated in animal models and extensive toxicology studies. The Company opened its first study site in its Phase 2a clinical trial to evaluate 12-week safety, tolerability and steady-state PK of IkT-148009 in untreated Parkinson's patients on 23 May, 2022. About Inhibikase (www.inhibikase.com) Inhibikase Therapeutics, Inc. (Nasdaq: IKT) is a clinical-stage pharmaceutical company developing therapeutics for Parkinson's disease and related disorders. Inhibikase's multi-therapeutic pipeline focuses on neurodegeneration and its lead program IkT-148009, an Abelson Tyrosine Kinase (c-Abl) inhibitor, targets the treatment of Parkinson's disease inside and outside the brain. Its multi-therapeutic pipeline is pursuing Parkinson's-related disorders of the brain and GI tract, orphan indications related to Parkinson's disease such as Multiple System Atrophy, and drug delivery technologies for kinase inhibitors such as IkT-001Pro, a prodrug of the anticancer agent Imatinib that the Company believes will provide a better patient experience with fewer on-dosing side-effects. The Company's RAMP™ medicinal chemistry program has identified a number of follow-on compounds to IkT-148009 to be potentially applied to other cognitive and motor function diseases of the brain. Inhibikase is headquartered in Atlanta, Georgia with offices in Boston, Massachusetts. Social Media Disclaimer Investors and others should note that the Company announces material financial information to investors using its investor relations website, press releases, SEC filings and public conference calls and webcasts. The Company intends to also use Twitter, Facebook, LinkedIn and YouTube as a means of disclosing information about the Company, its services and other matters and for complying with its disclosure obligations under Regulation FD.