COH34
目录号 : GC39282COH34 是一种有效且特异性的聚 (ADP-核糖) 糖水解酶 (PARG) 抑制剂,IC50为 0.37 nM。COH34 与 PARG 的催化结构域 (Kd= 0.547 μM) 结合,从而延长了 DNA 损伤处的 PARylation 并捕获了 DNA 修复因子。
Cas No.:906439-72-3
Sample solution is provided at 25 µL, 10mM.
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COH34 is a potent and specific poly(ADP-ribose) glycohydrolase (PARG) inhibitor with an IC50 of 0.37 nM. COH34 binds to the catalytic domain of PARG (Kd=0.547 μM), thereby prolonging PARylation at DNA lesions and trapping DNA repair factors[1].
[1]. Chen SH, et al. Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies. Sci Adv. 2019 Apr 10;5(4):eaav4340.
Cas No. | 906439-72-3 | SDF | |
Canonical SMILES | CC1=CC=C(S/N=C/C2=C3C=CC=CC3=CC=C2O)C=C1 | ||
分子式 | C18H15NOS | 分子量 | 293.38 |
溶解度 | DMSO: 16.67 mg/mL (56.82 mM) | 储存条件 | Store at -20°C,unstable in solution, ready to use. |
General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。 为了提高溶解度,请将管子加热至37℃,然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.4085 mL | 17.0427 mL | 34.0855 mL |
5 mM | 0.6817 mL | 3.4085 mL | 6.8171 mL |
10 mM | 0.3409 mL | 1.7043 mL | 3.4085 mL |
第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量) | ||||||||||
给药剂量 | mg/kg | 动物平均体重 | g | 每只动物给药体积 | ul | 动物数量 | 只 | |||
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DMSO母液配制方法: mg 药物溶于 μL DMSO溶液(母液浓度 mg/mL,
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1. 首先保证母液是澄清的;
2.
一定要按照顺序依次将溶剂加入,进行下一步操作之前必须保证上一步操作得到的是澄清的溶液,可采用涡旋、超声或水浴加热等物理方法助溶。
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Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies
Sci Adv 2019 Apr 10;5(4):eaav4340.PMID:30989114DOI:10.1126/sciadv.aav4340.
While poly(ADP-ribosyl)ation (PARylation) plays an important role in DNA repair, the role of dePARylation in DNA repair remains elusive. Here, we report that a novel small molecule identified from the NCI database, COH34, specifically inhibits poly(ADP-ribose) glycohydrolase (PARG), the major dePARylation enzyme, with nanomolar potency in vitro and in vivo. COH34 binds to the catalytic domain of PARG, thereby prolonging PARylation at DNA lesions and trapping DNA repair factors. This compound induces lethality in cancer cells with DNA repair defects and exhibits antitumor activity in xenograft mouse cancer models. Moreover, COH34 can sensitize tumor cells with DNA repair defects to other DNA-damaging agents, such as topoisomerase I inhibitors and DNA-alkylating agents, which are widely used in cancer chemotherapy. Notably, COH34 also efficiently kills PARP inhibitor-resistant cancer cells. Together, our study reveals the molecular mechanism of PARG in DNA repair and provides an effective strategy for future cancer therapies.
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.PMID:36053937DOI:10.1002/cnr2.1709.
Background: Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme in poly(ADP-ribose) (PAR) metabolism and a potential anticancer target. Many drug candidates have been developed to inhibit its enzymatic activity. Additionally, PDD00017273 is an effective and selective inhibitor of PARG at the first cellular level. Aims: Using human colorectal cancer (CRC) HCT116 cells, we investigated the molecular mechanisms and tumor biological aspects of the resistance to PDD00017273. Methods and results: HCT116RPDD , a variant of the human CRC cell line HCT116, exhibits resistance to the PARG inhibitor PDD00017273. HCT116RPDD cells contained specific mutations of PARG and PARP1, namely, PARG mutation Glu352Gln and PARP1 mutation Lys134Asn, as revealed by exome sequencing. Notably, the levels of PARG protein were comparable between HCT116RPDD and HCT116. In contrast, the PARP1 protein levels in HCT116RPDD were significantly lower than those in HCT116. Consequently, the levels of intracellular poly(ADP-ribosyl)ation were elevated in HCT116RPDD compared to HCT116. Interestingly, HCT116RPDD cells did not exhibit cross-resistance to COH34, an additional PARG inhibitor. Conclusion: Our findings suggest that the mutated PARG acquires PDD00017273 resistance due to structural modifications. In addition, our findings indicate that PDD00017273 resistance induces mutation and PARP downregulation. These discoveries collectively provide a better understanding of the anticancer candidate PARG inhibitors in terms of resistance mechanisms and anticancer strategies.