更新于：2024-09-19

AAK1

更新于：2024-09-19

基本信息

别名

AAK1、Adaptor-associated kinase 1、AP2 associated kinase 1

+ [3]

简介

Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis (PubMed:17494869, PubMed:11877457, PubMed:11877461, PubMed:12952931, PubMed:14617351, PubMed:25653444). Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1 (PubMed:17494869). Preferentially, may phosphorylate substrates on threonine residues (PubMed:11877457, PubMed:18657069). Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes (PubMed:12952931). Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes (PubMed:18657069). Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity (PubMed:21464124). (Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue.

关联

项与 AAK1 相关的药物

Pilavapadin

靶点

AAK1

作用机制

AAK1抑制剂

在研机构

Lexicon Pharmaceuticals, Inc. [+1]

原研机构

Lexicon Pharmaceuticals, Inc.

在研适应症

疱疹后神经痛 [+1]

非在研适应症

糖尿病周围神经性疼痛 [+1]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

SAT-3247

靶点

AAK1

作用机制

AAK1抑制剂

在研机构

Satellos Bioscience, Inc.

原研机构

Satellos Bioscience, Inc.

在研适应症

杜氏肌营养不良症 [+1]

非在研适应症-

最高研发阶段早期临床1期

首次获批国家/地区-

首次获批日期1800-01-20

SAT-3153

靶点

AAK1 x Protein kinases

作用机制

AAK1抑制剂 [+2]

在研机构

Satellos Bioscience, Inc.

原研机构

Satellos Bioscience, Inc.

在研适应症

杜氏肌营养不良症 [+1]

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 AAK1 相关的临床试验

NCT06565208 / Recruiting早期临床1期

Phase 1, Randomized, Double-blind, Placebo-controlled, Staggered, Parallel, Single and Multiple Ascending Dose and Food Effect Study to Evaluate the Safety and PK of Oral SAT-3247 in Healthy Volunteers and Participants With DMD

This is a first-in-human (FIH), Phase 1 study of orally administered SAT-3247 in healthy adult volunteers (HVs) and adult participants with DMD to determine safety, tolerability, pharmacokinetics and pharmacodynamics.

开始日期2024-08-21

申办/合作机构

Satellos Bioscience, Inc.

NCT06203002 / Recruiting临床2期

A Phase 2b, Dose-ranging, Randomized, Double-blind, PlacebO-controlled, Parallel-GRoup, MulticEnter Study in PatientS With Diabetic Peripheral Neuropathic Pain (PROGRESS)

Evaluation of the efficacy of LX9211 compared to placebo in reducing DPNP. Please see study website: https://diabeticpainstudy.com/

开始日期2023-11-29

申办/合作机构

Lexicon Pharmaceuticals, Inc.

NCT04662281 / Completed临床2期

A Phase 2, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of LX9211 in the Treatment of Postherpetic Neuralgia (RELIEF-PHN1)

Evaluation of the efficacy of LX9211 compared to placebo in reducing pain related to postherpetic neuralgia over an 11 week assessment period.

开始日期2020-12-29

申办/合作机构

Lexicon Pharmaceuticals, Inc.

100 项与 AAK1 相关的临床结果

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100 项与 AAK1 相关的转化医学

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0 项与 AAK1 相关的专利（医药）

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169

项与 AAK1 相关的文献（医药）

2024-12-31·Emerging Microbes & Infections

Numb-associated kinases regulate sandfly-borne Toscana virus entry

Article

作者: Luxenburg, Chen ; Borenstein-Auerbach, Nofit ; Yaffe, Yakey ; Maoz, Ben M ; Perlson, Eran ; Raved, Roey ; Subramaniam, Anand G ; Malis, Yehonathan ; Einav, Shirit ; Tadmor, Keshet ; Sklan, Ella H ; Katz, Rodolfo ; Moalem, Yarden ; Lustig, Yaniv ; Yoo, Ji Seung

Sandfly-borne Toscana virus (TOSV) is an enveloped tri-segmented negative single-strand RNA Phlebovirus. It is an emerging virus predominantly endemic in southwestern Europe and Northern Africa. Although TOSV infection is typically asymptomatic or results in mild febrile disease, it is neurovirulent and ranks among the three most common causes of summer meningitis in certain regions. Despite this clinical significance, our understanding of the molecular aspects and host factors regulating phlebovirus infection is limited. This study characterized the early steps of TOSV infection. Our findings reveal that two members of the Numb-associated kinases family of Ser/Thr kinases, namely adaptor-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK), play a role in regulating the early stages of TOSV entry. FDA-approved inhibitors targeting these kinases demonstrated significant inhibition of TOSV infection. This study suggests that AAK1 and GAK represent druggable targets for inhibiting TOSV infection and, potentially, related Phleboviruses.

2024-06-13·ACS Medicinal Chemistry Letters

Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

Article

作者: Shah, Ashish ; Schurer, Stephan C. ; Chaudhry, Sana ; Zhang, Ziming ; Castro, Jesus R. ; Feng, Yangbo ; Afaghani, Jumana ; Taylor, Justin ; Khurshid, Rabia ; Nicholls, Miah ; Totiger, Tulasigeri M.

STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases.Overexpression of STK17A is observed in many cancers.We identified a lead compound that is based on a quinazoline core.Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability.Compound 9 had an STK17A inhibitory IC50 of 23 nM.Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, resp.), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5.In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.

2024-03-01·European Journal of Medicinal Chemistry

Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2

Article

作者: Che, Hao ; Deng, Haowen ; Wang, Chenchen ; Gao, Yuan ; Yao, Xia ; Mao, Nian-Dong ; Xu, Yueying ; Hui, Zi ; Ye, Xiang-Yang ; Zhang, Hang

Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the μ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC₅₀ value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.

项与 AAK1 相关的新闻（医药）

2024-08-29

·新药前沿

IPF也疯狂：新药开发“三剑客”突围

First in Class类新药虽是全球生物医药公司的最高追求，但对于国内多数医药公司来说，以目前的实力可能还难以企及。follow策略仍旧是目前国内多数创新药开发者的首选。而在现实中，国内企业仍旧面临着follow（信息、研发等）速度慢、动态评估不科学和关键节点决策不果断等问题（或风险）。【中国follow式创新药系列】将通过一些案例的介绍，希望能够给国内生物医药公司follow First in Class类新药提供经验和思考。特发性肺纤维化（IPF）是一种主要发生在老年人群中的慢性、进行性、不可逆、纤维化和致命的慢性纤维化性间质性肺炎。全世界约有300万人患有此病，目前国内缺乏IPF发病率及患病率数据，在我国预计有40-60万患者，每年发病率新增11%。 IPF病因不明，病因多样，治疗方法不多，预后差，因此该领域新药研发远远不能满足临床需求。争食两强重磅市场份额自2014年10月FDA相续批准基因泰克（罗氏）的Esbriet（吡非尼酮）和勃林格殷格翰的Ofev（尼达尼布）用于治疗特发性肺纤维化（IPF），两强之间的市场份额之争异常激烈。以“孤儿药”地位获批并不影响Esbriet和Ofev能到达“重磅炸弹”级销售额的能力。Esbriet在美国失去独占保护的2021年实现了10.4亿美元的销售额（其中约7.32亿美元来自美国市场），而即将于2025年在美国失去专利保护的Ofev在2023年全球销售额更是达到35.10亿欧元（约38亿美元）。目前，在美国有4款Ofev仿制药获得FDA暂时性批准(Tentative Approval)等待原研专利到期后上市，而Esbriet 仿制药已上市的竞争者多达7家。在中国，据米内网数据显示，2023年中国城市公立医院、县级公立医院、城市社区中心以及乡镇卫生院（简称中国公立医疗机构）终端吡非尼酮、尼达尼布合计销售额超过9亿元，同比增长57.06%。两款产品快速增长的市场，再加上在中国已失去专利保护，同样面临着仿制药的激烈竞争：尼达尼布仿制药获批上市6家（齐鲁、人福普克、江苏万高、四川科伦、江苏豪森、石药恩必普）。另外还有瑞阳制药、沈阳红旗正在ANDA审评中。尽管吡非尼酮仿制药目前仅有北京凯因科技获批上市，不过正在ANDA审评中的厂家同样不少（包括重庆赛维、成都倍特药业、四川依科制药、山东华铂凯盛/安徽泰恩康、江苏知原、浙江金华康恩贝），此外，在吡非尼酮改良药物方面，浙江金华康恩贝和越洋医药分别正在开发吸入用吡非尼酮溶液和吡非尼酮双释片。有意思的是，还有3家公司正在开发吡非尼酮的me-too/better类药物：广州嘉越的舒非尼酮、广东东阳光的伊非尼酮和爱科百发AK3280。现有疗法局限性尽管机制不完全相同，吡非尼酮通过抑制细胞因子转化生长因子β(TGF-β)来抑制纤维化过程。而尼达尼布可广泛抑制成纤维细胞和肌成纤维细胞中的下游信号通路。这两种药物都能抑制成纤维细胞增殖、阻碍胶原蛋白的产生并减少纤维化介质的产生，有效改善肺功能和减缓疾病进展，但不可避免的是吡非尼酮和尼达尼布都会产生显著的不良反应，从而限制临床给药及其全部疗效潜力。如近期发表于《欧洲临床药理学杂志》的一项真实世界研究的系统评价与荟萃分析显示，吡非尼酮和尼达尼布的不良反应发生率分别高达56.4%和69.7%，因不良反应中断治疗率分别为16.6%和16.2%，IPF相关死亡率分别为13.4%和7.2%，全因死亡率分别为20.1%和16.6%。 IPF的发病机制是多方面的且目前尚未完全了解，再加上非尼酮和尼达尼布临床治疗的局限性，因此该领域更具疗效和安全性的新药研发对满足IPF临床未满足需求更加必需和紧迫。新药开发初露锋芒 IPF新药研发尽管屡屡遭遇失败挫折，但近期已有3款新机制的项目进入到临床试验晚期阶段，如能成功该领域有望取得新的突破。 Nerandomilast：PDE4B抑制剂勃林格殷格翰开发的Nerandomilast (BI 1015550) 是一种口服的选择性磷酸二酯酶4B (PDE4B) 抑制剂。抑制PDE4可提高细胞内环磷酸腺苷(cAMP)水平，减轻炎症和纤维化相关的炎症，这表明，激活cAMP通路可为治疗IPF提供新的靶点。除了抗炎作用外，Nerandomilast还在临床前模型中表现出抗纤维化作用，因为Nerandomilast抑制了TGF-β刺激的成纤维细胞转化为肌成纤维细胞。 Nerandomilast在IPF患者中开展的II期试验表明，该药物在预防肺功能下降方面取得了良好的效果，且安全性良好。然而，这项概念验证研究的局限性在于其持续时间为12周，样本量相对较小（147名患者，按2:1的比例随机分配接受BI1015550或安慰剂）。腹泻是所有患者（>10%的患者）中报告最多的事件，所有事件均报告为非严重事件。勃林格殷格翰目前正在进行Nerandomilast治疗IPF和进行性肺纤维化 (PPF) 的III期试验。国内海思科和人福医药也在布局选择性PDE4B抑制剂，其中海思科8月初发布公告称，其开发的HSK44459用于间质性肺疾病IND申请获得CDE批准，即将开展临床试验。 BMS-986278：LPA1拮抗剂百时美施贵宝于2011年斥资3.25亿美元收购Amira Pharmaceuticals，从而获得了强效小分子溶血磷脂酸（LPA）1拮抗剂候选药物BMS-986278。LPA通过溶血磷脂酸受体1（LPAR1）诱导成纤维细胞迁移/积聚和血管渗漏，从而促进纤维化的进展。BMS-986278可阻断循环和局部的成纤维细胞被招募至损伤部位；抑制上皮细胞通过上皮间质转化（EMT）分化为成纤维细胞。 BMS-986278的II期研究表明，与安慰剂相比，BMS-986278治疗26周可将预测用力肺活量百分比(ppFVC)的下降率降低62%。BMS-986278在两个治疗组中均耐受性良好，不良事件发生率（包括胃肠道副作用发生率）和治疗中断率与安慰剂组相当。 BMS-986278治疗IPF 的III期试验正在进行中。而安进同类项目AMG 670紧随其后也正在进行IIb期临床试验。 Bexotegrast：αvβ6和αvβ1整合素双选择性抑制剂 Pliant Therapeutics开发的Bexotegrast(PLN-74809)是一种口服小分子αvβ6和αvβ1整合素双选择性抑制剂。αvβ6和αvβ1整合素在正常组织中的表达水平非常低，但在特发性肺纤维化患者的肺组织中表达上调。这两种整合素都是TGF-β的激活剂，可导致胶原蛋白生成增加，并最终导致这些组织纤维化。通过阻断αvβ6和αvβ1对TGF-β的激活，Bexotegrast可能减缓并可能阻止此类患者群体的纤维化进展。 IIa期研究表明，Bexotegrast治疗的患者总肺胶原减少，而安慰剂组的总肺胶原增加，表明纤维化可能逆转。与安慰剂组相比，接受Bexotegrast治疗的患者在所有时间点均表现出用力肺活量(FVC)改善和咳嗽严重程度降低。Bexotegrast耐受性良好，没有药物相关的严重不良事件(SAE)且没有停药。 Bexotegrast治疗IPF 的II/III期试验正在进行中。除上述项目外，目前还有多达十多种不同作用机制的IPF新药进入到临床试验阶段，期待未来有更多新突破。注：本文已刊载于8月22日《医药经济报》往期推荐 01 Nav1.8抑制剂fast-follow者恒瑞快速调转船头 02 吸入PDE3/4抑制剂fast-follow凑齐3家：正大天晴领跑，恒瑞延缓后被海思科追赶 03 DPP1抑制剂fast-follow者海思科的完美“变现” 04 神经疼痛新靶点AAK1：IIa期POC已成功，引国内多家公司fast-follow布局 05 PDE4B抑制剂fast-follow者海思科和人福，紧追勃林格殷格翰本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

孤儿药专利到期

2024-08-28

·新药前沿

PDE4B抑制剂fast-follow者海思科和人福，紧追勃林格殷格翰

First in Class类新药虽是全球生物医药公司的最高追求，但对于国内多数医药公司来说，以目前的实力可能还难以企及。follow策略仍旧是目前国内多数创新药开发者的首选。而在现实中，国内企业仍旧面临着follow（信息、研发等）速度慢、动态评估不科学和关键节点决策不果断等问题（或风险）。【中国follow式创新药系列】将通过一些案例的介绍，希望能够给国内生物医药公司follow First in Class类新药提供经验和思考。 PDE4有4个亚型，进而导致口服Pan-PDE4抑制剂的安全性问题成为临床难以克服的治疗障碍，寻求更具选择性的PDE4B正在成为生物医药公司新药研发的突破口。相较于传统pan-PDE4抑制剂，选择性PDE4B抑制剂预期在保留抗炎效果的基础上，能减少胃肠道、中枢神经等不良反应。勃林格殷格翰作为PDE4B抑制剂开发的先驱，Nerandomilast（BI 1015550）目前已进入到治疗特发性肺纤维化和进行性纤维化性间质性肺疾病Ⅲ期临床试验阶段。来源：doi:10.3389/fphar.2022.838449 2022年5月，勃林格殷格翰在《新英格兰医学杂志》（NEJM）上发表了BI 1015550的II期顶线数据，并在美国胸科学会（ATS）国际会议以摘要形式进行了介绍：12周数据显示特发性肺纤维化（IPF）患者的肺功能下降速度有所降低。就在勃林格殷格翰公布BI 1015550的II期顶线数据结果之后一个月，两家中国公司海思科和人福已悄悄进行专利布局，对BI 1015550进行fast-follow。今年8月8日，海思科发布公告称，其开发的选择性PDE4B抑制剂HSK44459用于间质性肺疾病IND申请获得CDE批准，即将开展临床试验。人福与海思科同一时间对PDE4B抑制剂进行了专利布局，如果项目开发顺利应与海思科处于同一起跑线（人福今年6月IND申请项目HW071021片，推测有可能是PDE4B抑制剂？待后续核实确认）。往期推荐 01 Nav1.8抑制剂fast-follow者恒瑞快速调转船头 02 吸入PDE3/4抑制剂fast-follow凑齐3家：正大天晴领跑，恒瑞延缓后被海思科追赶 03 DPP1抑制剂fast-follow者海思科的完美“变现” 04 神经疼痛新靶点AAK1：IIa期POC已成功，引国内多家公司fast-follow布局本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

临床2期临床申请临床3期

2024-08-13

·Firstwordpharma

Lexicon cuts workforce in half as it shifts focus to once-rejected diabetes hopeful

Lexicon Pharmaceuticals said Tuesday it will reallocate resources towards the potential US launch of Zynquista for diabetes at the end of the year and “right-size” its promotional activities for heart failure medicine Inpefa. Both drugs contain the same active ingredient of sotagliflozin, an SGLT-1/2 dual inhibitor.The company will also lay off more than 75 employees, accounting for about half of its workforce, to realise about $40 million in cost-savings for 2025. According to CEO Mike Exton, the strategic shift reflects a “plan to allocate resources… and focus on where we have the potential to lead and succeed.” Lexicon is expecting an FDA decision by December 20 on Zynquista to improve glycaemic control in adults with type 1 diabetes and chronic kidney disease. The US regulator rejected Lexicon’s efforts to win approval for Zynquista in 2019, though the drug was cleared that year in the EU for patients with type 1 diabetes and a body mass index of at least 27 who failed to achieve adequate glycaemic control despite optimal insulin therapy. With the cost-savings initiative, Lexicon plans to make a “proper investment” in Zynquista’s launch, pending a positive decision from the FDA. The reduced expenses will also enable the company to ensure that all of its R&D programmes are fully funded, including a Phase III study of sotagliflozin in hypertrophic cardiomyopathy and an ongoing Phase IIb trial in diabetic neuropathic pain for LX9211, a small molecule inhibitor of adaptor-associated kinase 1.

上市批准临床2期