CHIR99021
| CHIR99021 | |
|---|---|
| |
| IUPAC名 6-((2-((4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)ethyl)amino)nicotinonitrile | |
| 别名 | Laduviglusib[1] |
| 识别 | |
| CAS号 | 252917-06-9 
|
| PubChem | 9956119 |
| ChemSpider | 8131728 |
| SMILES |
|
| ChEBI | 91091 |
| KEGG | D12196 |
| IUPHAR配体 | 8014 |
| 性质 | |
| 化学式 | C22H18Cl2N8 |
| 摩尔质量 | 465.34 g·mol−1 |
| 若非注明，所有数据均出自标准状态（25 ℃，100 kPa）下。 | |
CHIR99021是一种化合物，可作为酶GSK-3的抑制剂[2]。它已被证明，在涉及将一种细胞类型转化为另一种细胞类型的分子生物学应用中有效[3][4]。
CHIR99021和丙戊酸的混合物，代号FX-322，据称可增加内耳干细胞的增殖，可能使毛细胞重新生长。毛细胞对听觉重要，并会因慢性噪音暴露或衰老而丢失[5][6][7]。2023年，由于IIb期临床研究中未能显著改善获得性感觉神经性耳聋（SNHL）患者的言语感知能力，FX-322中止开发[8][9]。
该物质已被用作化学品混合液的一部分，以将衰老的人类细胞变回年轻细胞（以转录组年龄衡量），而不将它们完全变成未分化的诱导性多能干细胞[10]。
2024年，在小鼠急性肺损伤模型中，研究发现CHIR99021可通过抑制GSK3，促进肺泡上皮细胞增殖和肺再生[11]，并在大鼠模型中，触发部分肝切除的肝再生过程[12]。2025年，研究发现CHIR99021可通过抑制GSK3β，诱导FHIT缺失型肺癌细胞凋亡[13]。
参见
[编辑]参考文献
[编辑]- ^ Laduviglusib. PubChem. [2025-03-20].
- ^ An WF, Germain AR, Bishop JA, Nag PP, Metkar S, Ketterman J, et al. Discovery of Potent and Highly Selective Inhibitors of GSK3b. Probe Reports from the NIH Molecular Libraries Program.. Bethesda (MD): National Center for Biotechnology Information (US). 2012-04-16. PMID 23658955.
- ^ Singh VK, Kumar N, Kalsan M, Saini A, Chandra R. Mechanism of Induction: Induced Pluripotent Stem Cells (iPSCs). Journal of Stem Cells. 2015, 10 (1): 43–62. PMID 26665937.
- ^ Takeda Y, Harada Y, Yoshikawa T, Dai P. Chemical compound-based direct reprogramming for future clinical applications. Bioscience Reports. June 2018, 38 (3). PMC 5938430
. PMID 29739872. doi:10.1042/BSR20171650.
- ^ US 2017226477,Karp JM, Yin X, Succi MD, Langer RS,“Compositions and methods for epithelial stem cell expansion and culture”,发表于10 August 2017,指定于Massachusetts Institute of Technology和The Brigham and Women's Hospital, Inc.
- ^ US 11033546,Loose C, McLean W, Harrison M, Jirousek MR,“Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor”,发表于15 June 2021,指定于Frequency Therapeutics Inc.
- ^ McLean WJ, Yin X, Lu L, Lenz DR, McLean D, Langer R, et al. Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Reports. February 2017, 18 (8): 1917–1929. PMC 5395286 . PMID 28228258. doi:10.1016/j.celrep.2017.01.066 （英语）.
- ^ Frequency Therapeutics To Discontinue FX-322 Development Program; To Immediately Reduce Headcount. Nasdaq. 2023-02-13 [2025-03-20].
- ^ Experimental hearing loss drug fails to show benefit in clinical trial. Healthy Hearing. 2023-02-15 [2025-03-20].
- ^ Yang JH, Petty CA, Dixon-McDougall T, Lopez MV, Tyshkovskiy A, Maybury-Lewis S, Tian X, Ibrahim N, Chen Z, Griffin PT, Arnold M, Li J, Martinez OA, Behn A, Rogers-Hammond R, Angeli S, Gladyshev VN, Sinclair DA. Chemically induced reprogramming to reverse cellular aging. Aging. July 2023, 15 (13): 5966–5989. PMC 10373966 . PMID 37437248. doi:10.18632/aging.204896.
- ^ Fernandes R, Barbosa-Matos C, Borges-Pereira C, Carvalho ALRT, Costa S. Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model. Int J Mol Sci. 2024-01-26, 25 (2): 1279. PMC 10816825 . PMID 38279281. doi:10.3390/ijms25021279.
- ^ Khurana C, Sapra V, Silakari P, Panesar G, Chaudhary M, Gurjeet Singh T, Bedi O. Exploration of CHIR99021 by GSK-3β inhibition for triggering the liver regeneration process in partially hepatectomized rats. J Appl Pharm Sci. 2024-08-05, 14 (8): 206–215. doi:10.7324/JAPS.2024.186136.
- ^ Tao, S., Pu, Y., Yang, E.J.; et al. Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair. Exp Mol Med. 2025-01-06, 57: 167–183. doi:10.1038/s12276-024-01374-0.
