更新于：2024-11-01

AAK1

更新于：2024-11-01

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

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 / Active, not 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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171

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.

2024-12-01·European Journal of Medicinal Chemistry

Synthesis of 3-heteroaryl-pyrrolo[2,3-b]pyridines as potent inhibitors of AP-2-associated protein kinase 1 (AAK1) with antiviral activity

Article

作者: Agrawal, Aditi ; Einav, Shirit ; Voet, Arnout ; Ravi, Nitha Panikkassery ; Van Eynde, Wout ; Karim, Marwah ; Dehaen, Wim ; Schols, Dominique ; Nhu Tran, Do Hoang ; De Jonghe, Steven

Inhibition of AP-2-associated protein kinase 1 (AAK1) has been shown to be a promising avenue for the development of broad-spectrum antiviral agents. On a previously described AAK1 inhibitor based on a pyrrolo[2,3-b]pyridine scaffold, the concept of isosterism was applied, by replacing a carboxamide linker by various five-membered heterocycles. It led to the discovery of a novel series of AAK1 inhibitors with IC₅₀ values in the low nM range, that also displayed antiviral activity against the dengue virus and Venezuelan equine encephalitis virus.

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 ; Feng, Yangbo ; Castro, Jesus R. ; Afaghani, Jumana ; Taylor, Justin ; Khurshid, Rabia ; Totiger, Tulasigeri M. ; Nicholls, Miah

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.

项与 AAK1 相关的新闻（医药）

2024-10-30

·新药前沿

周围神经痛新靶点药物开发复苏

随着人口老龄化，以糖尿病性周围神经病理性疼痛（DPNP）、带状疱疹后神经痛（PHN）为代表的周围神经病理性疼痛（pNP）的发病率逐年增加。与此同时，过去20年对疼痛和痛觉的神经生物学研究也不断取得积极的进展，生物制药行业在探索不同机制pNP新药开发方面初见成效。尽管已获批上市超过20年，加巴喷丁、普瑞巴林仍旧是周围神经病理性疼痛临床治疗的金标准。普瑞巴林作为第二代钙离子通道调节剂，与加巴喷丁相比，增强了与α2-δ 亚基的亲和力，滴定和起效更快，但仍旧不可避免嗜睡、头晕、周围性水肿、视物模糊等不良反应的发生。第三代钙离子通道调节剂，通过提高对中枢神经系统α2δ亚基靶点亲和力，可进而提高疗效和降低不良反应发生率。2款第三代钙离子通道调节剂近年相续获得批准上市：第一三共开发的Tarlige（Mirogabalin/美洛加巴林）2019年1月首次在日本获批上市用于神经性疼痛治疗。2024年6月在我国获批进口上市用于DPNP（商品名德力静）。美洛加巴林对钙离子通道α2δ亚基具有较高的亲和力，且其与α2δ-1亚基解离缓慢，与α2δ-2亚基解离快速，该机制可能是其具有较好的镇痛治疗效果和较少不良反应的原因。海思科开发的思美宁（Crisugabalin/克利加巴林）于2024年5月在我国获批上市用于DPNP，并随后于7月获批PHN，克利加巴林（HSK16149 ）抑制[ 3H ]加巴喷丁与α2δ的结合亚单位与美洛加巴林相当，作用比普瑞巴林强23倍。克利加巴林是全球首个无需滴定的第三代中枢神经系统钙离子通道调节剂，也是国内首个获批DPNP适应症的药物。随着第三代钙离子通道调节剂在国内获批上市，我国DPNP临床治疗也正在迎来新格局。 2024年5月，我国发布的《国家基层糖尿病神经病变诊治指南（2024版）》就建议，对于DPNP，普瑞巴林或度洛西汀可作为首选，加巴喷丁、美洛加巴林、克利加巴林也可作为一种有效的初始治疗药物。衔接蛋白2相关激酶1（AAK1）是丝氨酸/苏氨酸激酶Ark1/Prk1家族成员，在调节受体内吞作用中发挥作用。 AAK1被确定为治疗神经性疼痛的潜在治疗靶点是基于2016年的一项研究结果：AAK1基因敲除（KO）小鼠对小鼠福尔马林模型的急性疼痛期（I期）反应正常，但对持续疼痛期（II期）反应减弱。AAK1基因敲除小鼠在脊神经结扎（SNL）手术后也没有出现触觉异常性疼痛。 AAK1抑制剂治疗神经性疼痛的机制（行为和电生理学）与α2肾上腺素能信号传导有关，α2肾上腺素能信号传导是人类已知的抗伤害性通路。 Lexicon与百时美施贵宝（BMS）合作开发的AAK1抑制剂LX9211（BMS-986176）具有治疗DPNP、PHN和神经性疼痛潜力。 2023年6月，LX9211治疗DPNP的疗效和安全性IIa期概念验证研究（RELIEF-DPN1）结果发表在《糖尿病护理》杂志：对于中度至重度DPNP患者，低剂量LX9211治疗6周后，与安慰剂相比，达到了主要疗效终点。虽然高剂量LX9211的结果也表明疼痛在数值上有所减轻，但并未达到预先规定的显著性水平，这可能是因为高剂量组TEAE发生率较高，导致治疗中断有关。尽管两种剂量的LX9211发生TEAE的几率都高于安慰剂，但低剂量LX9211组总体上耐受性良好。尽管II期概念验证研究存在治疗时间相对较短和仅在美国招募参与者限制，但主要疗效终点得到满足，支持将AAK1转化为治疗神经病理性疼痛的新型治疗靶点，如在动物模型中观察到的，使用AAKI抑制剂LX9211可缓解神经病理性疼痛。基于概念验证研究结果而正在开展的剂量范围探索IIb期PROGRESS试验预计于2025年第二季度公布结果。与此同时，Lexicon与百时美施贵宝也正在筹划LX9211治疗DPN推进到Ⅲ期临床试验。 LX9211的IIa期概念验证研究成功开始引起国内多家公司fast-follow布局，包括海思科、人福、扬子江药业旗下的上海海雁等。海思科开发的HSK36357用于周围神经病理性疼痛I期试验于今年5月结束，上海海雁的YZJ-1495盐酸盐胶囊正在进行神经病理性疼痛I期试验。尽管尚未公布研发项目信息，推测可能是AAK1抑制剂。 2022年1月，Biohaven公司（该公司已于2022年10月被辉瑞收购）与比利时天主教鲁汶大学（KU Leuven）药物设计和发现中心（CD3）与离子通道研究实验室（LICR）宣布，签署独家全球许可和研究协议，开发和商业化first-in-class的TRPM3拮抗剂，以解决全球越来越多的慢性疼痛患者问题。BHV-2100是基于天主教鲁汶大学研究平台开发的一种口服小分子TRPM3拮抗剂。 TRPM3是天主教鲁汶大学LICR发现的治疗疼痛的新靶点。 TRPM3是一种参与疼痛信号传导的Ca2+通透性非选择性阳离子通道，在背根神经节（DRG）和三叉神经节的痛觉神经元中高度表达，在疼痛感知中起关键作用，可能是内源性疼痛缓解途径的下游靶点。动物实验数据表明TRPM3在神经性疼痛的自发性疼痛和热痛觉过敏中发挥作用，而且位于脊髓、中枢突起或DRG神经元细胞体中的TRPM3在调节热敏感性方面也发挥着重要作用。与TRPM3在疼痛中的作用一致，天主教鲁汶大学的研究数据表明，BHV-2100可以减轻动物模型中的疼痛行为，而不会产生其他疼痛疗法和机制所见的严重不良反应。 2024年5月，Biohaven在公司2024年投资者研发日活动介绍了已完成的BHV-2100的I期研究药代动力学和安全性数据。结果表明，该药物吸收迅速，20分钟内即可达到治疗浓度。单剂量高达500mg时，耐受性良好，超过了预期的治疗剂量，远高于EC90浓度。这些发现为BHV-2100进入临床试验提供了有力的证据支持，可用于治疗急性偏头痛和疼痛，是一种对中枢神经系统副作用非常小的非阿片类药物疗法。 Biohaven计划于2024年下半年启动偏头痛急性治疗的II期研究和疼痛的概念验证研究（POC）。Biohaven也在筹备提交BHV-2100用于慢性疼痛IND 计划。在国内，深圳晶蛋生物医药已开始进行TRPM3靶点的抗体专利布局。热休克蛋白90（HSP90）是一种普遍存在的信号转导调节剂，Hsp90抑制剂作为癌症治疗药物已获得临床成功（全球首款HSP90抑制剂Jeselhy已于2022年在日本获批上市用于治疗癌症化疗后进展的胃肠道间质瘤）。然而，Reata Pharmaceuticals公司（该公司已于2023年9月被渤健收购）尝试把Hsp90抑制剂推进到疼痛领域。 Reata Pharmaceuticals开发（从堪萨斯大学获得授权）的Cemdomespib（RTA901）是一种高效、选择性口服小分子Hsp90 C端调节剂。Cemdomespib可与Hsp90的C端结合，从而增加细胞保护基因和分子伴侣基因（包括Hsp70）的转录和 Hsp70蛋白的表达。调节HSP90和诱导HSP70有可能减轻糖尿病神经痛。在过去十年中，大量研究证据表明，通过诱导Hsp70可改善糖尿病周围神经病变和快速发作的脱髓鞘性神经病变。Cemdomespib是一种进入临床研究的第二代新型药物，在人体研究中表现出了良好的药代动力学和安全性。Cemdomespib具有改善病因与蛋白聚集无关的周围神经病方面的疗效。 Cemdomespib对DNDP患者的安全性和有效性的II期研究目前正在研究中。内容来源于网络，如有侵权，请联系删除。

上市批准

2024-10-22

·GlobeNewswire-Health Care

Lexicon Announces Completion of Screening in Phase 2B Progress Study of LX9211 in Diabetic Peripheral Neuropathic Pain (DPNP)

Top-line Data Now Anticipated in Q1 2025 LX9211 has previously received Fast Track designation from the U.S. Food and Drug Administration (FDA) for DPNP THE WOODLANDS, Texas, Oct. 22, 2024 (GLOBE NEWSWIRE) -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) today announced that it has closed screening and expects to complete enrollment ahead of schedule in PROGRESS (A Phase 2b, Dose-ranging, Randomized, Double-blind, PlacebO-controlled, Parallel-GRoup, MulticEnter Study in PatientS with Diabetic Peripheral Neuropathic Pain) studying LX9211, an orally-delivered, potent, selective, investigational small molecule inhibitor of adaptor-associated kinase 1 (AAK1). The Company also updated its expectations for the timing of anticipated top-line data, from the second quarter of 2025 to the first quarter of 2025. “We are excited to be ahead of schedule for a near-term completion of PROGRESS for LX9211, with top-line data now anticipated in Q1 of next year,” said Craig Granowitz, M.D., Ph.D., Lexicon’s senior vice president and chief medical officer. “There have been no new, non-opioid medications approved for neuropathic pain in more than two decades, and there is an urgent need for novel treatment options. We believe that LX9211 has the potential to positively impact the lives of people suffering with neuropathic pain and we thank the investigators, study sites, Lexicon clinical team members and especially the patients for their participation in this important study.” PROGRESS commenced in December of 2023 with the goal of enrolling adult patients with a diagnosis of diabetes (type 1 or type 2) with moderate to severe DPNP, with patients allowed to continue their current pain therapy. The primary endpoint of PROGRESS is a reduction of Average Daily Pain Score (ADPS) at 8 weeks. About Lexicon Pharmaceuticals Lexicon is a biopharmaceutical company with a mission of pioneering medicines that transform patients’ lives. Through the Genome5000™ program, Lexicon’s unique genomics target discovery platform, Lexicon scientists studied the role and function of nearly 5,000 genes and identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to treat disease safely and effectively. Lexicon has commercially launched one of these medicines, INPEFA® (sotagliflozin) in the United States, and has a pipeline of other promising drug candidates in discovery and clinical and preclinical development in neuropathic pain, diabetes and metabolism and other indications. For additional information, please visit www.lexpharma.com. About LX9211 Discovered using Lexicon’s unique approach to gene science, LX9211 is a potent, orally delivered, selective, investigational small molecule inhibitor of AAK1. Lexicon identified AAK1 in its target discovery efforts as a promising approach for the treatment of neuropathic pain. Preclinical studies of LX9211 demonstrated central nervous system penetration and reduction in pain behavior in models of neuropathic pain without affecting opiate pathways. LX9211 received Fast Track designation from the U.S. Food and Drug Administration for development in diabetic peripheral neuropathic pain. Safe Harbor Statement This press release contains “forward-looking statements,” including statements relating to Lexicon’s financial position and long-term outlook on its business, including the commercialization of its approved products and the clinical development of, regulatory filings for, and potential therapeutic and commercial potential of LX9211 and its other drug candidates. In addition, this press release also contains forward looking statements relating to Lexicon’s growth and future operating results, discovery, development and commercialization of products, strategic alliances and intellectual property, as well as other matters that are not historical facts or information. All forward-looking statements are based on management’s current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including Lexicon’s ability to meet its capital requirements, successfully commercialize its approved products, successfully conduct preclinical and clinical development and obtain necessary regulatory approvals of its other drug candidates on its anticipated timelines, achieve its operational objectives, obtain patent protection for its discoveries and establish strategic alliances, as well as additional factors relating to manufacturing, intellectual property rights, and the therapeutic or commercial value of its approved products and other drug candidates. Any of these risks, uncertainties and other factors may cause Lexicon’s actual results to be materially different from any future results expressed or implied by such forward-looking statements. Information identifying such important factors is contained under “Risk Factors” in Lexicon’s annual report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission. Lexicon undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise. For Investor and Media Inquiries:Lisa DeFrancesco Lexicon Pharmaceuticals, Inc.lexinvest@lexpharma.com

快速通道临床2期

2024-10-10

·新药前沿

“有新无创”式中国“新药”的窘境

关注新药，直击前沿！没有对比就没有伤害！更重要的是，没有对比，就难以正视自己的差距，进而寻求破解之策！分享2篇近期刊发于Nature Reviews Drug Discovery的文章图表数据：第一篇：Development of Chinese innovative drugs in the USA 2007-2023年中国创新药（innovative drugs）开展临床试验情况（来源于ClinicalTrials.gov）。 1、启动临床试验数量 2、申办者分布情况 3、临床试验开展现状 4、临床试验成功率在此期间，在美国进行试验的6种中国创新药物获得了美国药品食品监督管理局（FDA）的批准，分别为：泽布替尼（zanubrutinib, 2019年首次批准）、西达基奥伦塞（ciltacabtagene autoleucel, 2022）、本维莫德（benvitimod, 2022）、特瑞普利单抗（toripalimab, 2023）、呋喹替尼（fruquintinib, 2023）和艾贝格司亭α（efbemalenograstim alfa, 2023）第二篇：Comparative analysis of FDA approvals by top 20 pharma companies (2014-2023) 在2014年至2023年：FDA批准了全球TOP 20制药公司176种新药。其中83种属于同类首创药物（first-in-class）。这也就意味着，过去10年全球TOP 20制药公司获得FDA批准新药平均数量8.8种（剔除通过上市后收购药物获得这一数字为7.15种）。而且还是在TOP 20制药公司获批新药份额从72%（2014年）下降到40%（2023年）取得的数据。思考：很显然，中国创新药近年来尽管取得长足进展，但是：国内仍存在许多Pharma或者Biotech仅仅是通过follow方式Me-too项目的现象，这种“有新无创”式的“新药”基本不可能跨出国门（从国内众多“新药”的研发区域布局如临床试验开展和专利申请等可知）。更何况，全球领先医药公司在新药开发过程中项目升级迭代导致国内企业follow错误难以调转船头也时有发生。在药物研发领域，做到“新”是很容易的事情，尤其是在浩瀚的化合物中筛选不同结构，但最终能否实现具有自身临床优势的“创造性“才是关键。中国医药行业经历2016年仿制药大洗牌，再到本轮资本寒冬下的创新药大洗牌之后，或许才会真正起航。而谁会是经历两轮洗礼之后的幸存者呢？！ “新药前沿”格言大型制药公司领导者必须解决六个研发关键问题：清晰度、灵活性、责任、团队承诺、标准和奖励。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 First in Class心衰靶点RXFP1诺华、BMS失利后，礼来、AZ继续前行 04 DPP1抑制剂fast-follow者海思科的完美“变现” 05 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 06 让癌细胞分裂时“毙命”，KIF18A靶点启航 07 PDE4B抑制剂fast-follow者海思科和人福，紧追勃林格殷格翰 08 IPF也疯狂：新药开发“三剑客”突围 09 SHP2遭遇大药企“退货潮”：罗氏、赛诺菲、艾伯维、BMS 10 百时美施贵宝新药开发的毒理学评价之道 11 恒瑞急性疼痛新药HRS-2129获批临床，布局新一代NaV1.8抑制剂，兵贵神速本文由「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！

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