PDD 00017273 is a highly selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), with IC₅₀ and Kd values of 26nM and 1.45nM, respectively[1]. PDD 00017273 induces apoptosis by modulating PARG-related signaling pathways[2]. In addition, PDD 00017273 can increase the sensitivity of cancer cells to radiotherapy and chemotherapy[3-4].
In vitro, treatment of preosteoblastic MC3T3-E1 cells with PDD 00017273 (1μM) significantly increases intracellular poly(ADP-ribose) (PAR) levels while promoting alkaline phosphatase (ALP) activity and mineralization. Moreover, PDD 00017273 upregulates the mRNA expression levels of osteocalcin (Ocn) and bone sialoprotein (Bsp), as well as the transcriptional inducers osterix (Osx) and activating transcription factor 4 (Atf4), thereby accelerating the osteoblast differentiation process in MC3T3-E1 cells[5]. Long-term treatment of human colorectal cancer cells HCT116 with PDD 00017273 (10μM and 30μM) induces resistance, forming the HCT116-resistant PDD 00017273 cell line (HCT116RPDD). In HCT116RPDD cells, the PARG gene undergoes a Glu352Gln mutation, and the PARP1 gene undergoes a Lys134Asn mutation, with a significant reduction in PARP1 protein levels[6].
References:
[1] James DI, Smith KM, Jordan AM, et al. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Nov 18;11(11):3179-3190.
[2] Mori Y, Akizuki Y, Honda R, et al. Intrinsic signaling pathways modulate targeted protein degradation. Nat Commun. 2024 Jul 2;15(1):5379.
[3] Fabbrizi MR, Nickson CM, Hughes JR, et al. Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence. Cell Death Dis. 2024 Feb 17;15(2):150.
[4] Ali R, Alblihy A, Miligy IM, et al. Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers. Oncogene. 2021 Apr;40(14):2496-2508.
[5] Sasaki Y, Nakatsuka R, Inouchi T, et al. Inhibition of Poly (ADP-Ribose) Glycohydrolase Accelerates Osteoblast Differentiation in Preosteoblastic MC3T3-E1 Cells. Int J Mol Sci. 2022 May 2;23(9):5041.
[6] Tsuda K, Kurasaka C, Ogino Y, et al. Genomic and biological aspects of resistance to selective poly(ADP-ribose) glycohydrolase inhibitor PDD00017273 in human colorectal cancer cells. Cancer Rep (Hoboken). 2023 Feb;6(2):e1709.
PDD 00017273是一种高选择性的，聚（ADP-核糖）糖水解酶（PARG）抑制剂，IC50值和Kd值分别为 26nM和1.45nM[1]。PDD 00017273通过调节PARG相关的信号通路来诱导细胞凋亡[2]。此外，PDD 00017273还可增加癌细胞对放疗和化疗的敏感性[3-4]。
在体外，PDD 00017273（1μM）处理小鼠前成骨细胞MC3T3-E1细胞，可显著增加细胞内聚腺苷二磷酸核糖（PAR）水平，同时促进细胞碱性磷酸酶（ALP）活性和矿化能力。此外，PDD 00017273还可上调成骨细胞分化标志物骨钙素（Ocn）和骨桥蛋白（Bsp）的mRNA表达水平，以及转录诱导因子osterix（Osx）和激活转录因子4（Atf4）的mRNA表达水平，从而加速MC3T3-E1细胞的成骨细胞分化过程[5]。PDD00017273（10μM和30μM）长期处理人结直肠癌细胞HCT116，诱导其产生耐药性，形成HCT116耐药PDD00017273细胞系（HCT116RPDD）。HCT116RPDD细胞中PARG基因发生Glu352Gln突变，PARP1基因发生Lys134Asn突变，同时PARP1蛋白水平显著降低[6]。