ALK 的化学诱导降解。
Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).
机构信息
Department of Biological Chemistry & Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
Department of Pediatric Hematology and Oncology , Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School , Boston , Massachusetts 02215 , United States.
出版信息
J Med Chem. 2018 May 10;61(9):4249-4255. doi: 10.1021/acs.jmedchem.7b01655. Epub 2018 Apr 24.
Abstract
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).
摘要
我们介绍了第一种能够诱导间变性淋巴瘤激酶 (ALK) 降解的小分子降解剂的开发，包括在非小细胞肺癌 (NSCLC)、间变大细胞淋巴瘤 (ALCL) 和神经母细胞瘤 (NB) 细胞系中。这些降解剂是通过将已知的嘧啶基 ALK 抑制剂 TAE684 或 LDK378 与 cereblon 配体来那度胺偶联而成。我们证明，在某些细胞类型中，药物转运蛋白 ABCB1 的表达会降低降解剂的效力。此外，蛋白质组学分析表明，这些化合物还促进了其他激酶的降解，包括 PTK2（FAK）、Aurora A、FER 和 RPS6KA1（RSK1）。
相似文献
1
Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).ALK 的化学诱导降解。
J Med Chem. 2018 May 10;61(9):4249-4255. doi: 10.1021/acs.jmedchem.7b01655. Epub 2018 Apr 24.
2
Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC).通过蛋白水解靶向嵌合体（PROTAC）诱导间变性淋巴瘤激酶（ALK）的蛋白降解。
Biochem Biophys Res Commun. 2018 Oct 28;505(2):542-547. doi: 10.1016/j.bbrc.2018.09.169. Epub 2018 Sep 28.
3
Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK).间变性淋巴瘤激酶（ALK）的蛋白水解靶向嵌合体（PROTACs）。
Eur J Med Chem. 2018 May 10;151:304-314. doi: 10.1016/j.ejmech.2018.03.071. Epub 2018 Mar 27.
4
SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.SHP2 抑制恢复对 ALK 抑制剂耐药的 ALK 重排非小细胞肺癌的敏感性。
Nat Med. 2018 May;24(4):512-517. doi: 10.1038/nm.4497. Epub 2018 Mar 5.
5
Discovery of a PROTAC targeting ALK with in vivo activity.发现一种具有体内活性的靶向 ALK 的 PROTAC。
Eur J Med Chem. 2021 Feb 15;212:113150. doi: 10.1016/j.ejmech.2020.113150. Epub 2021 Jan 2.
6
Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.开发布加替尼降解剂（SIAIS117）作为治疗 ALK 阳性癌症耐药的潜在药物。
Eur J Med Chem. 2020 May 1;193:112190. doi: 10.1016/j.ejmech.2020.112190. Epub 2020 Feb 29.
7
Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib.基于结构的 SIAIS001 的发现，作为一种从阿来替尼构建的口服生物利用度 ALK 降解剂。
Eur J Med Chem. 2021 May 5;217:113335. doi: 10.1016/j.ejmech.2021.113335. Epub 2021 Mar 11.
8
The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC).间变性淋巴瘤激酶（ALK）在非小细胞肺癌（NSCLC）中的作用和治疗靶点。
Mol Cancer. 2018 Feb 19;17(1):52. doi: 10.1186/s12943-018-0810-4.
9
Safety and Tolerability of Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer.间变性淋巴瘤激酶抑制剂在非小细胞肺癌中的安全性和耐受性。
Drug Saf. 2019 Feb;42(2):199-209. doi: 10.1007/s40264-018-0771-y.
10
Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects.ALK 的药理学抑制剂通过靶标作用诱导免疫原性细胞死亡。
Cell Death Dis. 2021 Jul 16;12(8):713. doi: 10.1038/s41419-021-03997-x.
引用本文的文献
1
Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.基于 Cereblon 的 PROTAC 的合成、生物学评价及临床试验
Commun Chem. 2025 Jul 29;8(1):218. doi: 10.1038/s42004-025-01598-9.
2
Development of PROTACs for targeted degradation of oncogenic TRK fusions.用于靶向降解致癌性TRK融合蛋白的PROTACs的开发。
bioRxiv. 2025 Jun 24:2025.06.18.660465. doi: 10.1101/2025.06.18.660465.
3
Advancing Design Strategy of PROTACs for Cancer Therapy.用于癌症治疗的PROTACs的先进设计策略
MedComm (2020). 2025 Jun 25;6(7):e70258. doi: 10.1002/mco2.70258. eCollection 2025 Jul.
4
Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search.利用广泛的构象搜索构建PROTAC介导的三元复合物结构分布图谱。
J Chem Inf Model. 2025 Jul 14;65(13):6939-6948. doi: 10.1021/acs.jcim.5c00102. Epub 2025 Jun 23.
5
Recent advances in focal adhesion kinase (FAK)-targeting antitumor agents.聚焦粘附激酶（FAK）靶向抗肿瘤药物的最新进展。
RSC Adv. 2025 Jun 20;15(26):20957-20984. doi: 10.1039/d5ra01880c. eCollection 2025 Jun 16.
6
ALK in cancer: from function to therapeutic targeting.癌症中的间变性淋巴瘤激酶：从功能到治疗靶点
Nat Rev Cancer. 2025 May;25(5):359-378. doi: 10.1038/s41568-025-00797-9. Epub 2025 Mar 7.
7
Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons.探索PROTACs在癌症治疗中的应用：进展、挑战与未来展望
Food Sci Nutr. 2025 Feb 1;13(2):e70011. doi: 10.1002/fsn3.70011. eCollection 2025 Feb.
8
Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions.癌症治疗中的蛋白质降解靶向嵌合体：作用机制、设计、临床试验及未来方向。
Drug Deliv Transl Res. 2025 Jun;15(6):1801-1827. doi: 10.1007/s13346-024-01754-z. Epub 2024 Nov 29.
9
Targeted protein degradation: advances in drug discovery and clinical practice.靶向蛋白降解：药物发现和临床实践的进展。
Signal Transduct Target Ther. 2024 Nov 6;9(1):308. doi: 10.1038/s41392-024-02004-x.
10
Development of label-free light-controlled gene expression technologies using mid-IR and terahertz light.利用中红外和太赫兹光开发无标记光控基因表达技术。
Front Bioeng Biotechnol. 2024 Oct 11;12:1324757. doi: 10.3389/fbioe.2024.1324757. eCollection 2024.
本文引用的文献
1
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader.一种使用多激酶降解剂查询可降解激酶组的化学生物组学方法。
Cell Chem Biol. 2018 Jan 18;25(1):88-99.e6. doi: 10.1016/j.chembiol.2017.10.005. Epub 2017 Nov 9.
2
The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions.间变性淋巴瘤激酶（ALK）在非小细胞肺癌中的现状：新兴的治疗范例和未来方向。
Target Oncol. 2017 Dec;12(6):709-718. doi: 10.1007/s11523-017-0526-1.
3
Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.阿来替尼对比克唑替尼用于未经治疗的 ALK 阳性非小细胞肺癌。
N Engl J Med. 2017 Aug 31;377(9):829-838. doi: 10.1056/NEJMoa1704795. Epub 2017 Jun 6.
4
pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4 ubiquitin ligase.pSILAC 质谱分析揭示 ZFP91 是 IMiD 依赖性的 CRL4 泛素连接酶底物。
Nat Commun. 2017 May 22;8:15398. doi: 10.1038/ncomms15398.
5
First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.一线塞瑞替尼与铂类化疗用于晚期ALK 重排非小细胞肺癌（ASCEND-4）：一项随机、开放标签、III 期研究。
Lancet. 2017 Mar 4;389(10072):917-929. doi: 10.1016/S0140-6736(17)30123-X. Epub 2017 Jan 24.
6
The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.强效 ALK 抑制剂布加替尼（AP26113）在临床前模型中克服了对第一代和第二代 ALK 抑制剂的耐药机制。
Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25.
7
Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs.支撑EML4-ALK驱动癌症及其对靶向药物反应的分子机制。
Cell Mol Life Sci. 2016 Mar;73(6):1209-24. doi: 10.1007/s00018-015-2117-6. Epub 2016 Jan 11.
8
ALK inhibitors in non-small cell lung cancer: the latest evidence and developments.非小细胞肺癌中的ALK抑制剂：最新证据与进展
Ther Adv Med Oncol. 2016 Jan;8(1):32-47. doi: 10.1177/1758834015617355.
9
Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.洛拉替尼的ALK耐药突变L1198F导致对克唑替尼重新致敏。
N Engl J Med. 2016 Jan 7;374(1):54-61. doi: 10.1056/NEJMoa1508887. Epub 2015 Dec 23.
10
Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.用于降解致癌性BCR-ABL的模块化PROTAC设计
Angew Chem Int Ed Engl. 2016 Jan 11;55(2):807-10. doi: 10.1002/anie.201507634. Epub 2015 Nov 23.
Zotero 插件