Senexin B

Senexin B is a potent, selective, and orally available CDK8/CDK19 inhibitor, with IC50 values ranging from 24-50 nM[1].

CDK8 is cyclin-dependent kinase 8, and its closely related isoform is CDK19; it is an oncogenic transcription-regulating kinase. CDK8 plays an important role in the phenotype of pluripotent stem cells. In addition, CDK8 is a regulator of multiple transcriptional programs and is involved in oncogenesis; it has been identified as an oncogene in melanoma and colon cancer[1].

Senexin B is a potent, selective, and orally available CDK8/CDK19 inhibitor. Senexin B shows selectivity for CDK8 and CDK19, with Kd values of 140 nM and 80 nM, respectively. 1 mM Senexin B is completely soluble in 20% propylene glycol, and its solubility in water is 50 mM. In in vitro and in vivo experiments, Senexin B in the low nanomolar range inhibits CDK8/19 activity in an ATP-competitive manner[2]. In HT1080 cells, Senexin B inhibits IPTG-inducible p21-induced CMV-GFP expression[1].

In 8-week-old CB-17 SCID mice, intraperitoneal injection of 40 mg/kg Senexin B or control reagent for 5 days, followed by subcutaneous injection of 1×106 human A549 lung cancer cell line, Senexin B significantly slowed tumor growth. In female nude mice with orthotopic injection of MDA-MB-468 triple-negative breast cancer (TNBC) cells into the fat pad, daily pretreatment with 25 mg/kg Senexin B (i.p.) for 5 days produced potent and sustained inhibition of tumor growth[1].

References:
1.? Cdk8/cdk19 selective inhibitors and their use in anti-metastatic and chemopreventative methods for cancer. Publication number: WO2013116786 A1.
2.? Donald C. Porter, Mengqian Chen, Jiaxin Liang, et al. Abstract PR08: Targeting tumor microenvironment with selective small-molecule inhibitors of CDK8/19.