AP20187 is a synthetic dimerizer compound that can induce the dimerization of proteins engineered to contain FKBP (FK506-binding protein) domains[1]. AP20187 has been widely used in various biological research and therapeutic applications to control protein-protein interactions and regulate cellular processes[2]. By binding to FKBP domains, AP20187 can bring two proteins together, thereby activating or modulating specific signaling pathways or cellular functions[3]. This mechanism allows for precise control over biological processes, making it a powerful tool for studying complex cellular mechanisms and developing targeted therapies. AP20187 has shown significant potential in both cancer biology and regenerative medicine[4].
In vitro, treatment of HeLa cells modified with the iCasp9 gene with AP20187 (0.025–2.5nM) increased cell death in a concentration-dependent manner. Moreover, repeated treatments led to the development of resistance to AP20187[5]. In PC12 cells expressing the inducible trkA (ItrkA) receptor, AP20187 (1pM to 1.25μM) significantly induced neurite outgrowth in a time- and dose-dependent manner. AP20187 treatment also increased the phosphorylation levels of Erk1/2 and Akt in ItrkA-transduced PC12 cells to levels comparable to those induced by 50μg/mL nerve growth factor (NGF). Additionally, AP20187 treatment significantly increased neurite outgrowth by 3–4 times[6].
In vivo, 25- to 29-month-old INK-ATTAC transgenic mice were treated with AP20187 (10mg/kg) via intraperitoneal injection, three times per week for 8 weeks. AP20187 treatment significantly reduced the number of p16Ink4a-positive microglia in the CA3 region of the hippocampus and decreased microglial activation and inflammatory cytokine expression. AP20187 also improved cognitive function in aged mice, reducing the time and errors required to complete maze tests[7]. In 5- to 6-month-old INK-ATTAC transgenic mice, AP20187 (3.3mg/kg) was administered via intraperitoneal injection, three times per week for 4 weeks (total dose 40mg/kg). AP20187 treatment significantly decreased p16Ink4a expression in renal tissue, reduced the expression of senescence-associated genes (Cdkn2a, Cdkn2d, Cdkn1a), and lowered levels of proinflammatory cytokines and matrix metalloproteinases. AP20187 also improved renal function by reducing plasma creatinine levels, increasing renal blood flow and glomerular filtration rate, and reducing renal fibrosis and inflammatory cell infiltration[8].
References:
[1] Xiao H, Wang LL, Shu CL, et al. Establishment of a cell model based on FKBP12 dimerization for screening of FK506-like neurotrophic small molecular compounds. J Biomol Screen. 2006 Apr;11(3):225-35.
[2] Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016 Feb 11;530(7589):184-9.
[3] Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6.
[4] Pathak S, Singh V, Kumar N, et al. Inducible caspase 9-mediated suicide gene therapy using AAV6 vectors in a murine model of breast cancer. Mol Ther Methods Clin Dev. 2023 Nov 24;31:101166.
[5] Yuan Y, Ren H, Li Y, et al. Cell-to-cell variability in inducible Caspase9-mediated cell death. Cell Death Dis. 2022 Jan 10;13(1):34.
[6] Alfa RW, Tuszynski MH, Blesch A. A novel inducible tyrosine kinase receptor to regulate signal transduction and neurite outgrowth. J Neurosci Res. 2009 Sep;87(12):2624-31.
[7] Ogrodnik M, Evans SA, Fielder E, et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell. 2021 Feb;20(2):e13296.
[8] Kim SR, Puranik AS, Jiang K, et al. Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy. J Am Soc Nephrol. 2021 Aug;32(8):1987-2004.
AP20187是一种合成的二聚体化合物，能够诱导含有FKBP（FK506结合蛋白）结构域的蛋白质发生二聚化[1]。AP20187在多种生物学研究和治疗中被用于控制蛋白质-蛋白质相互作用和调节细胞过程[2]。通过与FKBP结构域结合，AP20187可以将两个蛋白质拉到一起，从而激活或调节特定的信号通路或细胞功能[3]。这种机制使得AP20187能够精确调控生物过程，成为研究复杂细胞机制和开发靶向治疗的强大工具。AP20187在癌症生物学和再生医学领域中研究中均显示出的潜力[4]。
在体外，AP20187（0.025-2.5nM）处理iCasp9基因修饰的HeLa细胞，HeLa细胞死亡率随AP20187浓度升高而增加，此外，多次给药处理导致细胞对AP20187产生耐药性[5]。AP20187（1pM至1.25μM）处理表达诱导型trkA（ItrkA）受体的PC12细胞，AP20187以时间和剂量依赖的方式显著诱导神经突起生长。AP20187处理导致ItrkA转导的PC12细胞中Erk1/2和Akt的磷酸化水平升高，与50μg/mL神经营养因子（NGF）处理相当。此外，AP20187处理显著增加了神经突起生长3-4倍[6]。
在体内，AP20187（10mg/kg）通过腹腔注射的方式对25-29个月大的INK-ATTAC转基因小鼠进行治疗，每周3天，连续治疗8周。AP20187处理显著减少了小鼠海马体CA3区域中p16Ink4a阳性的微胶质细胞数量，并降低了微胶质细胞的激活程度，减少了炎症因子的表达。AP20187处理还改善了老年小鼠的认知功能，减少了完成迷宫测试的时间和错误次数[7]。AP20187（3.3mg/kg）通过腹腔注射的方式对5-6个月大的INK-ATTAC转基因小鼠进行治疗，每周3次，连续治疗4周，总剂量为40mg/kg。AP20187处理显著降低了小鼠肾组织中p16Ink4a的表达，减少了衰老相关基因（Cdkn2a、Cdkn2d、Cdkn1a）的表达，并降低了促炎因子和基质金属蛋白酶的水平。AP20187还改善了肾功能，降低了血浆肌酐水平，提高了肾血流和肾小球滤过率，减少了肾纤维化和炎症细胞浸润[8]。