CTX-712 is a potent CDC2 like kinase (CLK) inhibitor with an IC50 value of 1.4nM [1]. CLK is associated with various neurodegenerative diseases, metabolic regulation, and viral infections [2]. CTX-712 can inhibit cancer survival and the growth of cancer cells [3].
In vitro, after 6 hours of treatment with CTX-712 on MOLM13 cells, the phosphorylation levels of SRSF2, SRSF4, and SRSF6 in the cells decreased in a dose-dependent manner, and apoptosis was induced. 72 hours of CTX-712 treatment inhibited the proliferation of acute myeloid leukemia cell lines (U937, THP1, MOLM13), with IC50 values of 71.3±12.5nM, 147±16.1nM, and 35.5±2.3nM, respectively [4]. CTX-712 also inhibited the proliferation of human myeloid K562 and MV-4-11 cells, with IC50 values of 0.15μM and 0.036μM, respectively. The IC50 value of CTX-712 for primary acute myeloid leukemia (AML) cells was 0.078μM, indicating its anti-leukemia effect [3].
In vivo, oral administration of CTX-712 (6.25-12.5mg/kg/day) for 2 weeks inhibited t inhibits tumor size in mice with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and improves survival rate [3].
References:
[1] Tang J, Xie Y, Huang J, et al. A critical update on the strategies towards small molecule inhibitors targeting Serine/arginine-rich (SR) proteins and Serine/arginine-rich proteins related kinases in alternative splicing. Bioorg Med Chem. 2022;70:116921.
[2] Qin Z, Qin L, Feng X, Li Z, Bian J. Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions. J Med Chem. 2021 Sep 23;64(18):13191-13211.
[3] Yoda A, Morishita D, Mizutani A, et al. CTX-712, a Novel Clk inhibitor targeting myeloid neoplasms with SRSF2 mutation[J]. Blood, 2019, 134: 404.
[4] Yang H, Fang Z, Wei Y, et al. CDC2-like Kinases (CLKs) Inhibition As a Novel Targeted Therapeutic Strategy in Myelodysplastic Syndromes (MDS)[J]. Blood, 2024, 144: 6691.
CTX-712是一种强效的cdc2相似激酶（CLK）抑制剂，IC50值为1.4nM [1]。CLK与多种神经退行性疾病、代谢调节以及病毒感染有关 [2]。CTX-712能够抑制癌细胞的存活和生长 [3]。
在体外实验中，CTX-712处理MOLM13细胞6小时后，细胞SRSF2、SRSF4和SRSF6的磷酸化水平呈剂量依赖性下降，并且诱导了凋亡。72小时的CTX-712处理抑制了急性髓系白血病细胞系（U937、THP1、MOLM13）的增殖，其IC50值分别为71.3±12.5nM、147±16.1nM和35.5±2.3nM [4]。CTX-712对人类髓系K562和MV-4-11细胞的增殖也有抑制作用，其IC50值分别为0.15μM和0.036μM。CTX-712对原发性急性髓系白血病（AML）细胞的IC50值为0.078μM，表明其具有抗白血病作用 [3]。
在体内实验中，口服给予CTX-712（6.25-12.5mg/kg/d）2周，能够抑制患有骨髓增生异常综合征（MDS）和急性髓系白血病（AML）的小鼠的肿瘤大小，并提高生存率 [3]。