YKL-5-124 TFA is a potent, selective, irreversible, and covalent CDK7 inhibitor with IC50 values of 53.5nM and 9.7nM for CDK7 and CDK7/Mat1/CycH, respectively[1]. YKL-5-124 TFA can reduce the phosphorylation level of RB protein in multiple myeloma cells, thereby decreasing the activity of E2F and regulating the cell cycle[2]. YKL-5-124 TFA has been widely used to inhibit tumor progression in both cell models and animal models[3].
In vitro, YKL-5-124 TFA treatment for 72 hours significantly inhibited the proliferation of NCCIT cells and TCam2 cells, with IC50 values of 121.1nM and 263.4nM, respectively[4]. Treatment with 250nM YKL-5-124 TFA for 24 hours significantly inhibited the cell cycle arrest of H929 cells and led to a deficiency in cellular glycolysis and a decrease in lactate production levels[5]. Treatment with 100nM YKL-5-124 TFA for 48 hours significantly inhibited the phosphorylation of the T-loop of CDK1 and CDK2 in the small cell lung cancer (SCLC) cell lines, impaired DNA replication, and led to DNA damage and the formation of micronuclei[6].
In vivo, YKL-5-124 TFA treatment via intraperitoneal injection (2.5mg/kg; three times a week, combined with JQ1 (25mg/kg; three times a week) for 25 days led to a significant suppression of tumor growth and extended survival in the IMR-32-xenograft mouse models[7].
References:
[1] Olson C M, Liang Y, Leggett A, et al. Development of a selective CDK7 covalent inhibitor reveals predominant cell-cycle phenotype[J]. Cell chemical biology, 2019, 26(6): 792-803. e10.
[2] Yao Y, Park W D, Morelli E, et al. Aberrant CDK7 Activity Drives the Cell Cycle and Transcriptional Dysregulation to Support Multiple Myeloma Growth: An Attractive Molecular Vulnerability[J]. Blood, 2021, 138: 2687.
[3] Yao Y, Park W D, Morelli E, et al. Targeting MM at the Nexus between Cell Cycle and Transcriptional Regulation Via CDK7 Inhibition[J]. Blood, 2020, 136: 1-2.
[4] Funke K, Düster R, Wilson P D G, et al. Transcriptional CDK inhibitors as potential treatment option for testicular germ cell tumors[J]. Cancers, 2022, 14(7): 1690.
[5] Yao Y, Ng J F, Park W D, et al. CDK7 controls E2F-and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma[J]. Blood, The Journal of the American Society of Hematology, 2023, 141(23): 2841-2852.
[6] Zhang H, Christensen C L, Dries R, et al. CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer[J]. Cancer cell, 2020, 37(1): 37-54. e9.
[7] Gao Y, Volegova M, Nasholm N, et al. Synergistic anti-tumor effect of combining selective CDK7 and BRD4 inhibition in neuroblastoma[J]. Frontiers in Oncology, 2022, 11: 773186.
YKL-5-124 TFA是一种强效、选择性、不可逆的共价CDK7抑制剂，对CDK7和CDK7/Mat1/CycH复合物的IC50值分别为53.5nM和9.7nM[1]。YKL-5-124 TFA能够降低多发性骨髓瘤细胞中RB蛋白的磷酸化水平，从而减弱E2F活性并调控细胞周期[2]。YKL-5-124 TFA已被广泛用于在细胞模型和动物模型中抑制肿瘤进展[3]。
在体外，YKL-5-124 TFA处理72小时显著抑制了NCCIT细胞和TCam2细胞的增殖，IC50值分别为 121.1nM和263.4nM[4]。使用250nM的YKL-5-124 TFA处理H929细胞24小时，显著抑制了细胞周期阻滞，并导致细胞糖酵解缺陷和乳酸生成水平下降[5]。使用100nM的YKL-5-124 TFA处理小细胞肺癌（SCLC）细胞系48小时，显著抑制了CDK1和CDK2的T环磷酸化，损害DNA复制，并导致DNA损伤和微核形成[6]。
在体内，通过腹腔注射YKL-5-124 TFA（2.5mg/kg；每周三次）联合JQ1（25mg/kg；每周三次）治疗25天，显著抑制了IMR-32异种移植小鼠模型中的肿瘤生长，并延长了小鼠生存期[8]。