Dasatinib (BMS-354825)

Dasatinib (BMS-354825) is a highly potent and orally-bioavailable multi-target tyrosine kinase inhibitor with IC₅₀ values of 0.4nM for BCR-ABL, 0.5nM for SRC-family kinases, 100nM for c-KIT, and 180nM for PDGFR-β^[1]. Dasatinib readily crosses the blood–brain barrier and is widely used as a tool compound to investigate oncogenic kinase signaling and central nervous system disorders such as Alzheimer’s disease^[2]. In addition, Dasatinib has been reported to ameliorate diabetic kidney disease and aging-related metabolic dysfunction^[3-4].

In vitro, treatment of primary keloid dermal fibroblasts with 1–10nM Dasatinib for 24h selectively eliminated SA-β-gal- and p16-positive senescent cells in a dose-dependent manner and concomitantly reduced procollagen and p16 protein expression^[5]. Pre-incubation of BV2 microglial cells, primary mouse microglia, and primary astrocytes with 100–250nM Dasatinib for 30min–2h, followed by LPS stimulation (200ng/ml–1µg/ml) for 5.5h, significantly suppressed pro-inflammatory cytokine expression and attenuated the inflammatory response^[6].

In vivo, weekly intraperitoneal injections of Dasatinib (5mg/kg) combined with Quercetin (50mg/kg) were administered to C57BL/6J mice starting at 6, 14, or 18 months of age and continuing until 23 months; Dasatinib markedly mitigated age-related intervertebral disc degeneration^[7]. In 18-month-old BALB/c mice, Dasatinib (5mg/kg) plus Quercetin (50mg/kg) was given by oral gavage for 3 consecutive days every 2 weeks for 10 weeks. This regimen significantly reduced intestinal senescent cell burden and lowered inflammatory cytokine expression in the small and large intestines, while also reshaping the gut microbiota composition of aged mice ^[8].

References:
[1] Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004 Dec 30;47(27):6658-61.
[2] Cann ML, Herring LE, Haar LL, et al. Dasatinib Is Preferentially Active in the Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma. J Proteome Res. 2019 Jan 4;18(1):522-534.
[3] Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456.
[4] Islam MT, Tuday E, Allen S, et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging Cell. 2023 Feb;22(2):e13767.
[5] Darmawan CC, Hur K, Kusumaningrum N, et al. Dasatinib Attenuates Fibrosis in Keloids by Decreasing Senescent Cell Burden. Acta Derm Venereol. 2023 Apr 6;103:adv4475.
[6] Ryu KY, Lee HJ, Woo H, et al. Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling. J Neuroinflammation. 2019 Oct 26;16(1):190.
[7] Novais EJ, Tran VA, Johnston SN, et al. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun. 2021 Sep 3;12(1):5213.
[8] Saccon TD, Nagpal R, Yadav H, et al. Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice. J Gerontol A Biol Sci Med Sci. 2021 Oct 13;76(11):1895-1905.

Dasatinib (BMS-354825)是一种高效、口服生物利用度高的多靶点酪氨酸激酶抑制剂，对BCR-ABL、SRC家族激酶、c-KIT和PDGFR-β的IC₅₀分别为0.4nM、0.5nM、100nM和180nM^[1]。Dasatinib可透过血脑屏障，是研究肿瘤激酶信号及阿尔茨海默病等中枢神经系统疾病的重要工具药物^[2]。此外，Dasatinib还被证实可改善糖尿病肾病、代谢、衰老等功能^[3-4]。

在体外，在原代瘢痕疙瘩真皮成纤维细胞中，以1–10nM Dasatinib处理24h后，Dasatinib可选择性地清除SA-β-gal和p16阳性的衰老细胞，并呈剂量依赖地降低procollagen与p16蛋白表达^[5]。Dasatinib（100–250nM）预处理BV2小胶质细胞、小鼠原代小胶质细胞及原代星形胶质细胞30min–2h，随后以LPS（200ng/ml–1μg/ml）刺激5.5h，显著抑制促炎因子的表达，同时降低炎症反应^[6]。

在体内，Dasatinib（5mg/kg）联合Quercetin（50mg/kg）每周一次腹腔注射，用于处理6月龄、14月龄或18月龄的C57BL/6J小鼠，直至23月龄。Dasatinib显著减少了与年龄相关的椎间盘退变^[7]。Dasatinib（5mg/kg）联合Quercetin（50mg/kg），每2周经口灌胃给药3天，持续10周，用于处理18月龄BALB/c老龄小鼠模型。Dasatinib显著减少了肠道衰老细胞负荷，并降低炎症因子在小肠和大肠的表达。Dasatinib还能重塑老龄小鼠的肠道菌群结构^[8]。