CHIR99021
| CHIR99021 | |
|---|---|
| |
| IUPAC名 6-((2-((4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)ethyl)amino)nicotinonitrile | |
| 別名 | Laduviglusib[1] |
| 識別 | |
| CAS號 | 252917-06-9 
|
| PubChem | 9956119 |
| ChemSpider | 8131728 |
| SMILES |
|
| ChEBI | 91091 |
| KEGG | D12196 |
| IUPHAR配體 | 8014 |
| 性質 | |
| 化學式 | C22H18Cl2N8 |
| 摩爾質量 | 465.34 g·mol−1 |
| 若非註明，所有數據均出自標準狀態（25 ℃，100 kPa）下。 | |
CHIR99021是一種化合物，可作為酶GSK-3的抑制劑[2]。它已被證明，在涉及將一種細胞類型轉化為另一種細胞類型的分子生物學應用中有效[3][4]。
CHIR99021和丙戊酸的混合物，代號FX-322，據稱可增加內耳幹細胞的增殖，可能使毛細胞重新生長。毛細胞對聽覺重要，並會因慢性噪音暴露或衰老而丟失[5][6][7]。2023年，由於IIb期臨床研究中未能顯著改善獲得性感覺神經性耳聾（SNHL）患者的言語感知能力，FX-322中止開發[8][9]。
該物質已被用作化學品混合液的一部分，以將衰老的人類細胞變回年輕細胞（以轉錄組年齡衡量），而不將它們完全變成未分化的誘導性多能幹細胞[10]。
2024年，在小鼠急性肺損傷模型中，研究發現CHIR99021可通過抑制GSK3，促進肺泡上皮細胞增殖和肺再生[11]，並在大鼠模型中，觸發部分肝切除的肝再生過程[12]。2025年，研究發現CHIR99021可通過抑制GSK3β，誘導FHIT缺失型肺癌細胞凋亡[13]。
參見
[編輯]參考文獻
[編輯]- ^ 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」,發表於10 August 2017,指定於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」,發表於15 June 2021,指定於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 （英語）.
- ^ 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.
