FT671 is a potent and selective inhibitor of ubiquitin-specific protease 7 (USP7) with an IC50 value of 52nM[1]. USP7 can deubiquitinate MDM2, resulting in a decrease in the intracellular level of p53[2]. FT671 has anti-tumor activity[3].
In vitro, pretreatment of A549 cells with FT671 (0-24µM) for 4h significantly promoted the degradation of intracellular SP1 and β-Catenin proteins[4]. Treatment of colorectal cancer HCT116 cells with FT671 (10µM) for 5min significantly attenuated intracellular protein ubiquitination under the condition of USP7 knockdown[5].
In vivo, oral treatment of MM.1S cell xenograft mice with FT671 (100, 200mg/kg) significantly inhibited the growth of tumors in mice in a dose-dependent manner and was well tolerated[6].
References:
[1] Tanguturi P, Kim K S, Ramakrishna S. The role of deubiquitinating enzymes in cancer drug resistance[J]. Cancer chemotherapy and pharmacology, 2020, 85(4): 627-639.
[2] Park H B, Baek K H. Current and future directions of USP7 interactome in cancer study[J]. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2023, 1878(6): 188992.
[3] Cheng Y J, Zhuang Z, Miao Y L, et al. Identification of YCH2823 as a novel USP7 inhibitor for cancer therapy[J]. Biochemical Pharmacology, 2024, 222: 116071.
[4] Zhang K, Sun T, Li W, et al. Inhibition of USP7 upregulates USP22 and activates its downstream cancer-related signaling pathways in human cancer cells[J]. Cell Communication and Signaling, 2023, 21(1): 319.
[5] Steger M, Demichev V, Backman M, et al. Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale[J]. Nature communications, 2021, 12(1): 5399.
[6] Turnbull A P, Ioannidis S, Krajewski W W, et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors[J]. Nature, 2017, 550(7677): 481-486.
FT671是一种是有效的选择性泛素特异性蛋白酶7（USP7）抑制剂，IC50值为52nM[1]。USP7能将MDM2去泛素化，从而导致p53的细胞内水平下降[2]。FT671具有抗肿瘤活性[3]。
在体外，FT671（0-24µM）预处理A549细胞4h，显著促进了细胞内SP1和β-Catenin蛋白的降解[4]。FT671（10µM）处理结直肠癌HCT116细胞5min，在USP7敲低的条件下，显著减弱了细胞内蛋白质泛素化[5]。
在体内，FT671（100, 200mg/kg）通过口服治疗MM.1S细胞异种移植小鼠，以剂量依赖性方式显著抑制了小鼠体内肿瘤的生长，并具有良好的耐受性[6]。