选择性和强效的 c-Src 激酶 PROTAC 降解剂。
Selective and Potent PROTAC Degraders of c-Src Kinase.
机构信息
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
Department of Internal Medicine, University of Michigan, 1500 E. Medical Avenue, Ann Arbor, Michigan 48109, United States.
出版信息
ACS Chem Biol. 2024 Jan 19;19(1):110-116. doi: 10.1021/acschembio.3c00548. Epub 2023 Dec 19.
Abstract
Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib, the c-Src-directed ligand, with a conformation-selective analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src. We demonstrated a high degree of catalysis with our c-Src PROTACs. Using our c-Src PROTACs, we identified pharmacological advantages of c-Src degradation compared to inhibition with respect to cancer cell proliferation.
摘要
我们使用与 E3 连接酶配体偶联的达沙替尼，鉴定出一种强效且选择性的双重 Csk/c-Src PROTAC 降解剂。然后，我们用一种构象选择性类似物取代达沙替尼（c-Src 定向配体），该类似物稳定 c-Src 的αC-螺旋外构象。使用αC-螺旋外配体，我们鉴定出一种对 c-Src 具有高活性和选择性的 PROTAC。我们用 c-Src PROTAC 证明了高度的催化作用。使用我们的 c-Src PROTAC，我们发现与抑制相比，c-Src 降解在癌细胞增殖方面具有药理学优势。
相似文献
1
Selective and Potent PROTAC Degraders of c-Src Kinase.选择性和强效的 c-Src 激酶 PROTAC 降解剂。
ACS Chem Biol. 2024 Jan 19;19(1):110-116. doi: 10.1021/acschembio.3c00548. Epub 2023 Dec 19.
2
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones.E3 连接酶配体用于 PROTACs：它们是如何被发现的，以及如何发现新的配体。
SLAS Discov. 2021 Apr;26(4):484-502. doi: 10.1177/2472555220965528. Epub 2020 Nov 3.
3
Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation.基于 cereblon E3 连接酶设计、合成与生物评价的新型 BCR-ABL PROTACs 的发现。
Eur J Med Chem. 2021 Nov 5;223:113645. doi: 10.1016/j.ejmech.2021.113645. Epub 2021 Jun 25.
4
Discovery of E3 Ligase Ligands for Target Protein Degradation.E3 连接酶配体用于靶蛋白降解的发现。
Molecules. 2022 Oct 2;27(19):6515. doi: 10.3390/molecules27196515.
5
Leveraging Dual-Ligase Recruitment to Enhance Protein Degradation via a Heterotrivalent Proteolysis Targeting Chimera.利用双连接酶招募通过异三价靶向嵌合体增强蛋白质降解。
J Am Chem Soc. 2024 Dec 11;146(49):33675-33711. doi: 10.1021/jacs.4c11556. Epub 2024 Nov 28.
6
Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase.降解剂与抑制剂针对致癌性 BCR-ABL 激酶的药理学差异。
Sci Rep. 2018 Sep 10;8(1):13549. doi: 10.1038/s41598-018-31913-5.
7
Expansion of targeted degradation by Gilteritinib-Warheaded PROTACs to ALK fusion proteins.吉特替尼弹头 PROTACs 通过靶向降解扩展到 ALK 融合蛋白。
Bioorg Chem. 2024 Apr;145:107204. doi: 10.1016/j.bioorg.2024.107204. Epub 2024 Feb 14.
8
Workflow for E3 Ligase Ligand Validation for PROTAC Development.用于PROTAC开发的E3连接酶配体验证工作流程。
ACS Chem Biol. 2025 Feb 21;20(2):507-521. doi: 10.1021/acschembio.4c00812. Epub 2025 Feb 11.
9
Expanding the ligand spaces for E3 ligases for the design of protein degraders.拓展 E3 连接酶的配体空间以设计蛋白降解剂。
Bioorg Med Chem. 2024 May 1;105:117718. doi: 10.1016/j.bmc.2024.117718. Epub 2024 Apr 12.
10
Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders.优化针对 E3 连接酶 DCAF15 的有效配体，并评估其在杂双功能降解剂中的应用。
J Med Chem. 2024 Apr 11;67(7):5538-5566. doi: 10.1021/acs.jmedchem.3c02136. Epub 2024 Mar 21.
引用本文的文献
1
FDA-approved kinase inhibitors in PROTAC design, development and synthesis.FDA批准的用于PROTAC设计、开发和合成的激酶抑制剂。
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2542357. doi: 10.1080/14756366.2025.2542357. Epub 2025 Aug 12.
2
Characteristic roadmap of linker governs the rational design of PROTACs.连接子的特征路线图决定了PROTACs的合理设计。
Acta Pharm Sin B. 2024 Oct;14(10):4266-4295. doi: 10.1016/j.apsb.2024.04.007. Epub 2024 Apr 11.
3
Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC.新型 CEP1347-VHL-02 PROTAC 化合物选择性降解 MLK3，限制三阴性乳腺癌的致癌潜能。
J Med Chem. 2024 Sep 12;67(17):15012-15028. doi: 10.1021/acs.jmedchem.4c00577. Epub 2024 Aug 29.
本文引用的文献
1
Discovery of novel BTK PROTACs with improved metabolic stability via linker rigidification strategy.通过连接子刚性化策略发现具有改善代谢稳定性的新型 BTK PROTACs。
Eur J Med Chem. 2023 Jul 5;255:115403. doi: 10.1016/j.ejmech.2023.115403. Epub 2023 Apr 20.
2
Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions.催化降解物能有效解决 EML4-ALK 致癌融合中激酶结构域的突变。
J Med Chem. 2023 Apr 27;66(8):5524-5535. doi: 10.1021/acs.jmedchem.2c01864. Epub 2023 Apr 10.
3
Src: coordinating metabolism in cancer.Src：协调癌症中的代谢。
Oncogene. 2022 Nov;41(45):4917-4928. doi: 10.1038/s41388-022-02487-4. Epub 2022 Oct 10.
4
Current strategies for the design of PROTAC linkers: a critical review.PROTAC连接子设计的当前策略：批判性综述。
Explor Target Antitumor Ther. 2020;1(5):273-312. doi: 10.37349/etat.2020.00018. Epub 2020 Oct 30.
5
There's more to death than life: Noncatalytic functions in kinase and pseudokinase signaling.死亡不仅仅是生命的终结：激酶和拟激酶信号中非催化功能。
J Biol Chem. 2021 Jan-Jun;296:100705. doi: 10.1016/j.jbc.2021.100705. Epub 2021 Apr 22.
6
Paradoxical activation of c-Src as a drug-resistant mechanism.c-Src 悖论性激活作为耐药机制。
Cell Rep. 2021 Mar 23;34(12):108876. doi: 10.1016/j.celrep.2021.108876.
7
The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells.SH2结构域对三阴性乳腺癌细胞中c-Src功能的相关性
Cancers (Basel). 2021 Jan 26;13(3):462. doi: 10.3390/cancers13030462.
8
Structure and Characterization of a Covalent Inhibitor of Src Kinase.Src激酶共价抑制剂的结构与表征
Front Mol Biosci. 2020 May 19;7:81. doi: 10.3389/fmolb.2020.00081. eCollection 2020.
9
Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src.设计、合成及生物评价用于双重降解 IGF-1R 和 Src 的蛋白水解靶向嵌合体（PROTACs）
Molecules. 2020 Apr 23;25(8):1948. doi: 10.3390/molecules25081948.
10
Selective Proteolysis to Study the Global Conformation and Regulatory Mechanisms of c-Src Kinase.选择性蛋白水解研究 c-Src 激酶的整体构象和调控机制。
ACS Chem Biol. 2019 Jul 19;14(7):1556-1563. doi: 10.1021/acschembio.9b00306. Epub 2019 Jul 9.
Zotero 插件