Rocbrutinib

Advances in immunotherapy have ushered in a new era of treatment for follicular lymphoma (FL), particularly for patients who have experienced relapse after conventional chemotherapy regimens. This paradigm shift is characterized by the emergence of innovative therapies like CAR T-cell therapy and bispecific antibodies, which have demonstrated remarkable efficacy in targeting and eradicating lymphoma cells. CAR T-cell therapy represents a groundbreaking approach where a patient's own T-cells are genetically engineered to recognize and attack cancer cells. This personalized treatment has shown significant promise, especially for individuals who have undergone extensive previous therapies. One notable example is Axicabtagene ciloleucel (Yescarta), a CAR T-cell therapy approved for use in patients with relapsed or refractory follicular lymphoma. Clinical trials have highlighted its ability to induce durable remissions, with some patients experiencing long-term remission even after multiple prior therapies. LAS VEGAS, Nov. 28, 2024 /PRNewswire/ -- DelveInsight's ' Follicular Lymphoma Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline follicular lymphoma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the follicular lymphoma pipeline domain. Key Takeaways from the Follicular Lymphoma Pipeline Report DelveInsight's follicular lymphoma pipeline report depicts a robust space with 50+ active players working to develop 55+ pipeline therapies for follicular lymphoma treatment. Key follicular lymphoma companies such as Chia Tai Tianqing Pharmaceutical Group, Incyte Corporation, Mabworks, Johnson & Johnson Innovative Medicine, Nektar Therapeutics, Xynomic Pharmaceuticals, Merck Sharp & Dohme, Jiangsu HengRui Medicine Co., Ltd., ADC Therapeutics, Bristol-Myers Squibb, Swedish Orphan Biovitrum, Zhejiang DTRM Biopharma, Immpact Bio, Galapagos, Immunitas Therapeutics, Enterome, CRISPR Therapeutics, CHO Pharma, Shanghai Blueray Biopharma, BeiGene, AstraZeneca, AVM Biotechnology, Mustang Bio, Merck, Pell Bio-Med Technology, Schrodinger Inc., Sana Biotechnology, Poseida Therapeutics, OncoNano Medicine, Inc., Nurix Therapeutics, Inc., NovalGen, Pfizer, Xencor, Wellington Zhaotai Therapies, MEI Pharma, Sutro Biopharma, Synthekine, Verismo Therapeutics, Vincerx Pharma, Novartis, Century Therapeutics, Newave Pharmaceuticals, Bio-Path Holdings, Affimed GmbH, Iksuda Therapeutics, Allogene Therapeutics, Adicet Bio, Carna Biosciences, Inc., BeiGene, Boryung Pharmaceutical, Accutar Biotechnology, Atara Biotherapeutics, AbbVie, InnoCare Pharma, NeoImmuneTech, and others are evaluating new follicular lymphoma drugs to improve the treatment landscape. Promising follicular lymphoma pipeline therapies such as Parsaclisib, TQ-B3525, Tafasitamab, MIL62, Ibrutinib, AZD0486, NKTR-255, Abexinostat, Acalabrutinib, Zilovertamab vedotin, SHR2554, Nivolumab, Loncastuximab tesirine, Golcadomide, Emapalumab, DTRM-555, Capivasertib, IMPT 314, GLPG5101, IMT-009, EO2463, CTX112, CHO-H01, BR1733, BGB-16673, BGB-10188, AZD5492, AVM0703, MB106, MK-1026, PL001, SGR-1505, SC291, SC262, P-CD19CD20-ALLO1, ONM 501, NX-5948, NX 2127, NVG-111, Mevrometostat, Plamotamab, WZTL-002, Voruciclib, STRO001, SYNCAR-001 + STK-009, SynKIR-310, VIP-152, VAY736, CNTY-101, LP-168, BP1002, IOA-244, IKS 03, ALLO-501, ADI-001, AS-1763, BGB-21447, BR101801, AC676, ATA3219, ABBV-319, ABBV-101, ICP-B02, ICP-B05, C-CAR039, Efineptakin Alfa, and others are under different phases of follicular lymphoma clinical trials. In August 2024, the company expects to file a supplemental Biologics License Application for tafasitamab for the treatment of patients with FL who have failed at least one prior systemic anti-CD20 immunotherapy or chemo-immunotherapy by the end of 2024 based on the positive Phase III results. In June 2024, a consortium of Eugene Private Equity and Korea Development Bank Private Equity announced that they would acquire 80% of South Korean vaccine maker Boryung Biopharma Co. for 320 billion won (USD 231 million). In February 2024, Incyte announced that it had entered into an asset purchase agreement with MorphoSys AG, which gives Incyte exclusive global rights for tafasitamab. Incyte will now recognize revenue and cost for all US commercialization and clinical development and MorphoSys will no longer be eligible to receive future milestone, profit split and royalty payments. In September 2023, OncoNano Medicine, Inc. announced a clinical trial supply agreement with Regeneron for the use of Libtayo (cemiplimab), a PD-1 inhibitor, in the combination stage of the first human trial of ONM-501, a dual-activating STING (STimulator of INterferon Genes) agonist and lead therapeutic development candidate. The ONM-501 first-in-human trial is a multicenter Phase Ia/b dose escalation and dose expansion study of intratumoral ONM-501 as monotherapy and in combination with Libtayo in patients with advanced solid tumors and lymphomas. OncoNano is the sponsor of the clinical trial, and Regeneron will supply cemiplimab. In May 2023, Janssen Pharmaceutical Companies of Johnson & Johnson announced that it had entered into a worldwide collaboration and license agreement with Cellular Biomedicine Group Inc. (CBMG) to develop, manufacture, and commercialize next-generation chimeric antigen receptor (CAR) T-cell therapies for the treatment of B-cell malignancies. Under the terms of the agreement, CBMG will grant Janssen a worldwide license to develop and commercialize the CAR-T assets, except in Greater China. Janssen and CBMG will negotiate an option for Janssen to commercialize the products in the Chinese territory. Janssen will make an upfront payment of USD 245 million that will be accounted for in the second quarter as a research and development expense. Additional future payments will be based upon achieving certain development, regulatory, and sales milestones, as well as tiered royalty payments on worldwide net trade sales, excluding Greater China. Request a sample and discover the recent advances in follicular lymphoma treatment drugs @ Follicular Lymphoma Pipeline Report The follicular lymphoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage follicular lymphoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the follicular lymphoma clinical trial landscape. Follicular Lymphoma Overview Follicular lymphoma is a common type of non-Hodgkin lymphoma (NHL) that originates from B-cells, a kind of white blood cell responsible for producing antibodies. This cancer is characterized by the growth of abnormal lymphoid follicles, which can disrupt normal lymphatic function. While the exact causes of follicular lymphoma are not fully understood, certain factors may increase the risk, including age (most commonly affecting adults over 60), a family history of lymphoma, and potential environmental factors such as exposure to pesticides or chemicals. Symptoms of follicular lymphoma can vary widely but may include painless swelling of lymph nodes in the neck, armpit, or groin, unexplained weight loss, night sweats, fatigue, and fever. Some patients may remain asymptomatic for extended periods, as this type of lymphoma can progress slowly. Diagnosis typically involves a combination of physical examinations, blood tests, imaging studies (like CT scans), and a biopsy of affected lymph nodes. The biopsy helps determine the subtype and stage of the lymphoma, which is crucial for planning treatment. Treatment for follicular lymphoma depends on the stage of the disease and the patient's overall health. Options may include watchful waiting for asymptomatic cases, chemotherapy, immunotherapy (such as monoclonal antibodies), and targeted therapies. In some cases, stem cell transplants may be considered for patients with more aggressive forms or those who do not respond to initial treatments. Given the indolent nature of follicular lymphoma, ongoing management, and regular monitoring are vital for achieving the best possible outcomes. Find out more about follicular lymphoma treatment drugs @ Drugs for Follicular Lymphoma Treatment A snapshot of the Follicular Lymphoma Pipeline Drugs mentioned in the report: Learn more about the emerging follicular lymphoma pipeline therapies @ Follicular Lymphoma Clinical Trials Follicular Lymphoma Therapeutics Assessment The follicular lymphoma pipeline report proffers an integral view of the follicular lymphoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Follicular Lymphoma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Intra-articular, Intraocular, Intrathecal, Intravenous, Oral, Parenteral, Subcutaneous, Topical, Transdermal Therapeutics Assessment By Molecule Type: Oligonucleotide, Peptide, Small molecule Therapeutics Assessment By Mechanism of Action: Phosphatidylinositol 3 kinase delta inhibitors, Phosphatidylinositol 3 kinase gamma inhibitors, Emt protein-tyrosine kinase inhibitors, Interleukin 15 receptor agonists, Histone deacetylase inhibitors, Rad51 recombinase inhibitors, Agammaglobulinaemia tyrosine kinase inhibitors, Apoptosis stimulants, Cell cycle inhibitors, Tubulin inhibitors, Tubulin polymerisation inhibitors, Enhancer of zeste homolog 2 protein inhibitors, Antibody-dependent cell cytotoxicity, Programmed cell death 1 receptor antagonists, T lymphocyte stimulants, Alkylating agents, DNA cross-linking agents Key Follicular Lymphoma Companies: Chia Tai Tianqing Pharmaceutical Group, Incyte Corporation, Mabworks, Johnson & Johnson Innovative Medicine, Nektar Therapeutics, Xynomic Pharmaceuticals, Merck Sharp & Dohme, Jiangsu HengRui Medicine Co., Ltd., ADC Therapeutics, Bristol-Myers Squibb, Swedish Orphan Biovitrum, Zhejiang DTRM Biopharma, Immpact Bio, Galapagos, Immunitas Therapeutics, Enterome, CRISPR Therapeutics, CHO Pharma, Shanghai Blueray Biopharma, BeiGene, AstraZeneca, AVM Biotechnology, Mustang Bio, Merck, Pell Bio-Med Technology, Schrodinger Inc., Sana Biotechnology, Poseida Therapeutics, OncoNano Medicine, Inc., Nurix Therapeutics, Inc., NovalGen, Pfizer, Xencor, Wellington Zhaotai Therapies, MEI Pharma, Sutro Biopharma, Synthekine, Verismo Therapeutics, Vincerx Pharma, Novartis, Century Therapeutics, Newave Pharmaceuticals, Bio-Path Holdings, Affimed GmbH, Iksuda Therapeutics, Allogene Therapeutics, Adicet Bio, Carna Biosciences, Inc., BeiGene, Boryung Pharmaceutical, Accutar Biotechnology, Atara Biotherapeutics, AbbVie, InnoCare Pharma, NeoImmuneTech, and others. Key Follicular Lymphoma Pipeline Therapies: Parsaclisib, TQ-B3525, Tafasitamab, MIL62, Ibrutinib, AZD0486, NKTR-255, Abexinostat, Acalabrutinib, Zilovertamab vedotin, SHR2554, Nivolumab, Loncastuximab tesirine, Golcadomide, Emapalumab, DTRM-555, Capivasertib, IMPT 314, GLPG5101, IMT-009, EO2463, CTX112, CHO-H01, BR1733, BGB-16673, BGB-10188, AZD5492, AVM0703, MB106, MK-1026, PL001, SGR-1505, SC291, SC262, P-CD19CD20-ALLO1, ONM 501, NX-5948, NX 2127, NVG-111, Mevrometostat, Plamotamab, WZTL-002, Voruciclib, STRO001, SYNCAR-001 + STK-009, SynKIR-310, VIP-152, VAY736, CNTY-101, LP-168, BP1002, IOA-244, IKS 03, ALLO-501, ADI-001, AS-1763, BGB-21447, BR101801, AC676, ATA3219, ABBV-319, ABBV-101, ICP-B02, ICP-B05, C-CAR039, Efineptakin Alfa, and others. Dive deep into rich insights for new drugs for follicular lymphoma treatment, visit @ Follicular Lymphoma Drugs Table of Contents For further information on the follicular lymphoma pipeline therapeutics, reach out @ Follicular Lymphoma Treatment Drugs Related Reports Follicular Lymphoma Market Follicular Lymphoma Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key follicular lymphoma companies including Epizyme, Eisai, Bayer Healthcare Pharmaceuticals, Verastem Oncology, Gilead Sciences, TG Therapeutics, Bristol-Myers-Squibb, Roche, Incyte Corporation, Bristol Myers Squibb, ADC Therapeutics, MorphoSys, Nordic Nanovector, AbbVie, Regeneron Pharmaceuticals, Janssen Research & Development, Novartis, MEI Pharma, and BeiGene, among others. Non-Hodgkin Lymphoma Market Non-Hodgkin Lymphoma Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key Non-Hodgkin lymphoma companies, including Roche, Pfizer, Amgen, Novartis, Teva Pharmaceuticals, Genentech, ACD Therapeutics, among others. Non-Hodgkin Lymphoma Pipeline Non-Hodgkin Lymphoma Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key Non-Hodgkin lymphoma companies, including Novartis, AstraZeneca, Genentech, BioInvent, Genmab, SystImmune, Nordic Nanovector, Pacylex Pharmaceuticals, Artiva Biotherapeutics, Inc., Chipscreen Biosciences, Ltd., Timmune Biotech Inc., Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Gilead Sciences, Acerta Pharma BV, Adagene Inc, Conjupro Biotherapeutics, Inc., Rhizen Pharmaceuticals, Juventas Cell Therapy Ltd., Incyte Corporation, HUYA Bioscience International, SecuraBio, Genor Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Antengene Therapeutics Limited, Regeneron Pharmaceuticals, Jiangsu HengRui Medicine Co., Ltd., Xynomic Pharmaceuticals, Inc., BioTheryX, Inc., UWELL Biopharma, Kronos Bio, Bio-Thera Solutions, Spectrum Pharmaceuticals, Inc., Aptose Biosciences Inc., Miltenyi Biomedicine GmbH, Precision BioSciences, Inc., Teneobio, Inc., TCR2 Therapeutics, IGM Biosciences, Inc, among others. Diffuse Large B-cell Lymphoma Market Diffuse Large B-cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key DLBCL companies, including AbbVie, Genmab, Merck, Roche, Xencor, Janssen, Denovo Biopharma, Calithera Biosciences IMV, Biogen, Autolus Therapeutics, Allogene Therapeutics, Novartis, Miltenyi Biomedicine, Regeneron Pharmaceuticals, Debiopharm, Seagen, Takeda, AstraZeneca, Gilead Sciences, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . 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自2001年以来，蛋白激酶抑制剂格列卫（伊马替尼）是第一个获得FDA批准的药物，标志着针对BCR-ABL癌症治疗的重大突破，并预示着蛋白激酶抑制剂在肿瘤学和其他治疗领域的兴起。在过去的二十多年中，FDA共批准多达88种小分子抑制剂（截止到2024年8月30日），其中靶向蛋白激酶83种，靶向脂质激酶5种，详见图3。大多数获批的小分子激酶抑制剂通过结合目标的ATP结合位点来抑制蛋白激酶的活性。此外，变构抑制剂和共价抑制剂也是重要的发展方向，它们通过模拟蛋白激酶的自然调控机制，提供高特异性和治疗潜力。 根据早期报告，我们将小分子蛋白激酶抑制剂分为七个主要类别: I型：这些抑制剂可以与激活环中的氨基酸残基形成氢键，通常与ATP竞争性结合。 I½型：I½型抑制剂与ATP结合位点结合，但与I型抑制剂相比，与激活环的相互作用较弱。 II型：II型抑制剂与激酶的DFG-out构象结合，这通常在激酶的非活跃状态下观察到。这些抑制剂可以稳定这种非活跃状态，从而抑制激酶活性。 我们进一步将I½型和II型拮抗剂细分为A和B两个亚型。A型药物延伸过守门残基进入背部凹槽。相反，B型药物不延伸进入背部凹槽。根据不完整的数据表明，这种差异的可能意义是A型拮抗剂与其酶靶标结合的停留时间比B型阻断剂更长。 图1. Type I和TypeII结合位点 III型和IV型：变构抑制剂也是蛋白激酶抑制剂开发中的一个重要方向。根据变构抑制剂的结合位点是否靠近激酶的ATP结合位点，它们可以被分为III型和IV型抑制剂。III型抑制剂的结合位点靠近激酶的ATP结合位点，所有经过临床验证的MEK1/MEK2抑制剂都属于这一类。IV型抑制剂的结合位点则离ATP结合位点更远，包括ABL抑制剂如ABL001和AKT1抑制剂如MK-2206。 V型：V型抑制剂是针对性共价不可逆抑制剂，它们与激酶的特定氨基酸残基形成共价键，导致激酶永久性失活。 VI型：针对激酶的假激酶域。假激酶约占所有人类激酶的10%，被定义为缺乏一个或多个必需的保守催化基序的激酶，因此被预测为催化活性不活跃。尽管缺乏催化活性，假激酶的突变或其表达的失调已被与多种疾病联系起来，尤其是癌症和自身免疫疾病。因此，假激酶被认为是一类重要的新兴药物靶标。 Type VII型：靶向激酶的胞外结构域。 图2. Type III, IV, VI, VII抑制剂结合位点示意图 小分子蛋白激酶抑制剂（PKIs）的未来前景是充满希望的。随着新药的不断开发，大约有110种新型激酶处于临床试验阶段，这表明这一领域仍有很大的未开发潜力。未来的研究将集中在克服药物抗性、优化药代动力学和药效学特性以及个性化治疗上。联合疗法也将成为提高疗效的重要策略，通过将PKIs与其他治疗方法结合，可能有效地解决药物抗性问题。 图3. FDA批准的蛋白激酶抑制剂 ICE拥有用于筛选各种类型抑制剂的蛋白质，并且提供相应的筛选服务。进入下面的链接或通过我们的网站发送消息来了解更多信息：https://protein.ice-biosci.com/ ABL抑制剂 在2003年，Kuriyan和Superti-Furga的研究小组报告称，肉豆蔻酰基团参与了ABL1和ABL2激酶的自我调节：通过与ABL1激酶域C-叶中的内部“肉豆蔻酰结合位点/口袋”结合，共价连接到ABL1 N-末端的肉豆蔻酰基团，诱导了一个组装的非活跃状态，即SH1,SH2,SH3自抑单元。这种在ABL1中观察到的自我抑制机制可以与BCR片段融合后丧失，BCR片段取代了包含肉豆蔻酰化位点的ABL1的N-末端帽区域，从而导致BCR-ABL1的组成性激活。这种组装的非活跃状态与II型抑制剂如Imatinib和Olverembatinib不同，他们是通过直接结合DFG-out环构象来稳定激酶域的非活跃构象。通过与肉豆蔻酰位点相互作用来抑制ABL1激酶的药物将比ATP竞争性酪氨酸激酶抑制剂（TKIs）更具选择性，并且不会受到由于非靶激酶抑制而引起的不良事件的影响，因此可能具有良好的耐受性。 图4. ABL非活性状态下的最小自抑结构 图5. Rebastinib, Imatinib 和 Olverembatinib 为ABL II型抑制剂，ABL001为ABL type IV型抑制剂。 MEK1抑制剂 RAF/MEK/ERK通路是控制细胞生理的核心，其失调与许多癌症有关。因此，构成这一途径的蛋白一直受到强烈的药物发现和开发努力的影响。变构MEK抑制剂（Allosteric MEK inhibitors, MEKi）对RAF/ MEK/ERK通路信号通路具有复杂的作用，在临床上与BRAF抑制剂联合应用于恶性黑色素瘤。变构MEKi可以通过至少四种不同机制中的一种或多种来阻断RAF/MEK/ERK信号通路的激活：1)通过与uMEK结合并诱导阻止其与RAF结合；2)允许uMEK与RAF结合，使MEK稳定于抗磷酸化构象；3)通过阻止RAF释放pMEK，阻止ERK磷酸化；4)抑制游离pMEK以阻断其磷酸化ERK的能力。研究结果表明，MEK抑制剂除抑制MEK外还对BRAF/MEK复合物起抑制作用。 图6. MEK1变构抑制剂结合位点 图7. Selumetinib, Trametinib,和Avutometinibe 是III 型MEK1抑制剂 EGFR抑制剂 吉非替尼、厄洛替尼、阿法替尼和奥西替尼已被批准用于治疗EGFR激酶中存在激活突变的非小细胞肺癌，但由于迅速产生的耐药性，最常见的是由T790M突变产生许多不良反应。而EAI045不直接与EGFR的ATP结合位点竞争，而是结合到EGFR激酶域的“C-螺旋外”（C-helix out）构象的变构位点。在EGFR的不对称二聚体中，激活子亚基的C-叶与接收子亚基的N-叶相互作用，导致接收子亚基的C-螺旋向内移动，形成活跃构象。EAI045通过稳定C-螺旋在外的位置，阻止这种构象变化，从而抑制EGFR的活性。在突变型EGFR中，由于突变导致的构象变化，二聚体的形成可能更加频繁。EAI045通过阻断这种二聚体相互作用，减少了EGFR的激活。由于EAI045的高度选择性，它不太可能抑制其他非靶标激酶，这可能减少了因非特异性抑制而产生的不良反应。因此，EAI045提供了一种新的治疗策略，尤其适用于那些对传统ATP竞争性酪氨酸激酶抑制剂产生耐药的癌症患者，有望改善治疗效果并减少副作用。 图8. 变构型EGFR抑制剂的结构与结合方式 图9. Afatinib和Osimertinib 为EGFR共价抑制剂。BLU-945 为I型抑制剂，EAI-045是III抑制剂。 AKT抑制剂 AKT家族蛋白在细胞信号传导中扮演着核心角色，它们参与调节细胞增殖、存活、生长、代谢和血管生成等关键生物学过程。AKT属于AGC超家族，具有N端的PH结构域、激酶结构域和C端的调节区域。在生长因子的刺激下，PI3K的激活导致AKT转移到质膜上，并在T308和S473两个位点发生磷酸化，这一过程分别由PDK1和mTORC2催化，是AKT激活的关键步骤。在多种癌症中，AKT的激活常常是由于上游基因如PIK3CA的突变或扩增，以及PTEN的失活或丢失。此外，AKT基因本身的突变，如AKT1的E17K突变，也能导致其病理性激活，这种突变改变了AKT的脂质结合特异性，导致其在细胞膜上的异常定位和持续的信号传导。 最新的研究表明，在没有上游信号的情况下，AKT的PH结构域和激酶结构域之间的相互作用使其保持在一种自抑制的闭合状态，这阻止了PDK1对T308位点的磷酸化。而当接收到上游信号时，AKT会从这种自抑制状态转变为开放状态，使得磷酸化和激活成为可能。研究者通过对大量人类肿瘤样本的分析发现，PH-KD接触位点的突变在癌症中是存在的，这种突变破坏了PH和KD之间的相互作用，可能是AKT在癌症中激活的一种新机制。更重要的是，这些肿瘤特异性的突变不仅能够激活AKT，还可能改变肿瘤对变构AKT抑制剂的敏感性，这对于开发新的癌症治疗策略具有重要意义。 图10. ATK两种不同激活方式 图11. ATK变构抑制剂结合位点 图12. Capivasertib 为I 型AKT抑制剂，MK2206为IV AKT 型AKT抑制剂 JAK抑制剂 酪氨酸激酶2（TYK2）是Janus家族激酶（JAK）的成员，该家族还包括JAK1、JAK2和JAK3。JAK家族的非受体酪氨酸激酶在介导引起炎症的众多细胞因子信号传导中被认为是至关重要的。因此，JAK激酶的小分子抑制剂有望成为治疗各种严重炎症性和自身免疫性疾病的有效疗法。迄今为止，进入开发阶段的小分子JAK抑制剂绝大多数都是活性位点导向的抑制剂，它们通过结合JAK蛋白催化域（也称为JH1或“Janus同源1”域）的腺苷三磷酸（ATP）位点，阻止ATP、下游磷酸化和随之而来的信号传导途径，从而抑制激酶的催化活性。相比之下，BMS-986165选择性地结合TYK2的假激酶（JH2）域并通过变构机制抑制其功能，与之前的JAK抑制剂有所不同。由于这种独特的机制，BMS-986165与所有其他报道的JAK/TYK2抑制剂高度分化，实现前所未有的对TYK2的选择性，特别是对JAK1、JAK2和JAK3的选择性。 图13. BMS-986165与TYK2 JH2共晶结构 图14. BMS-986165为TYK2 VI 型抑制剂 BTK抑制剂 共价 BTK 抑制剂与 BTK 的 ATP 结合口袋内的半胱氨酸481（C481）残基形成不可逆的共价键。BTK 抑制导致 PLCγ2 等主要下游信号通路的激活受损，阻止恶性 B 细胞增殖并促进细胞凋亡。此类已批准的抑制剂包括伊布替尼、阿卡替尼和泽布替尼。临床前分析显示，共价抑制剂对 C481S 突变细胞几乎没有活性，对获得性耐药性的患者构成潜在挑战 。新的可逆BTK 抑制剂旨在最大限度地减少副作用和减少耐药性。Pirtobrutinib是目前FDA批准的第一个也是唯一一个非共价、可逆的BTK抑制剂。LP-168能够通过共价结合抑制野生型BTK和通过非共价结合抑制耐药突变型BTK，从而抑制B细胞受体信号传导通路，阻断B淋巴细胞的异常增殖、分化和存活。另一种针对 BTK 的新兴治疗选择是使用 BTK 降解剂NX-2127 目前正在复发或难治性 B 细胞恶性肿瘤中进行 1 期临床试验。 尽管大多数CLL (chronic lymphocytic leukemia) 患者对单药治疗 BTK 抑制剂有多年的反应，但需要持续治疗，并且最终会发展出 BTK 或 PLCγ2 的耐药突变。共价抑制剂特别容易受到 C481 突变的影响，因为它们依赖于与该残基的结合。非共价 BTK 抑制剂克服了这一限制，但仍易受到新型 BTK 激酶结构域突变的影响。BTK L528W、V416L 和 A428D 被归类为激酶功能受损的耐药突变，而 BTK C481S 和 T474I 被归类为激酶功能完整突变。BTK 降解剂仍在进行临床试验，但早期结果表明它们可以克服激酶受损和激酶熟练的获得性 BTK 耐药突变，但尚不清楚它们是否可以靶向下游 PLCγ2 激活突变。 图15. FDA批准的BTK抑制剂 图16. Ibrutinib和Acalabrutinib 为BTK共价抑制剂，Pirtobrutinib为BTK I型抑制剂 参考文献 1. Lu X, Smaill JB, Ding K. New Promise and Opportunities for Allosteric Kinase Inhibitors. Angew Chem Int Ed Engl. 2020 Aug 10;59(33):13764-13776. 2. 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