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.