IV-361 is an Orally Active and Selective CDK7 Inhibitor
Posted On 2021-08-19
Cyclin-dependent kinase 7 (CDK7) is a catalytic subunit of CDK activated kinase (CAK). CAK is a kinase complex that catalyzes T-ring phosphorylation and activates a variety of cyclin-related kinases, including CDK1, CDK2, CDK4, and CDK6. Importantly, CDK7 plays a role at the direct interface between important processes of cell cycle regulation and transcription. Moreover, compared with other CDKs, its activation requires two proteins, cyclin H and ring finger protein MAT1. Particularly, CDK7 is associated with the 10 subunit TFIIH complex. CDK7 regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). CDK7 can also phosphorylate CDK9, which together with ccnt1 forms a P-TEFb complex. In the cytoplasm, CDK7 contains the enzyme core of CDK activated kinase (CAK).
CDK7 is a component of the universal transcription factor TFIIH. Specifically, TFIIH phosphorylates the largest subunit of the CTD Pol II. Obviously, the main cell cycle phenotype caused by CDK7 inhibition is the accumulation of G1 or G2/M cells. And this accompanies a decrease in the number of S-phase cells. Besides, CDK7 also participates in mRNA processing by recruiting capping enzymes. Furthermore, it activates transcription by regulating the deposition and pause induction of histone markers related to active transcription. Here, we will introduce an orally active and selective CDK7 inhibitor, IV-361.
IV-361 is an Orally Active and Selective CDK7 Inhibitor.
First of all, IV-361 is an orally active and selective CDK7 inhibitor (Ki≤50 nM). Meanwhile, IV-361 has anti-tumor activity (US20190256531A1). Nonetheless, IV-361 has less inhibition on CDK2 (Ki≥1000 nM) or PLK1 (Ki≥5000 nM).
In the second place, IV-361 exhibits excellent IL-2 and IL-17 production inhibitory activity (all IC50≤100 nM) in periphery blood mononuclear cells (PBMC). Interestingly, IV-361 exhibits excellent HCT-116 cell growth inhibitory activity (GI50≤100 nM).
Last but not the least, IV-361 with 25 mg/kg/day by orally exhibits 46% or more rate of suppression of tumor volume in female BALB nude mice with HCT-116.
All in all, IV-361 is an orally active and selective CDK7 inhibitor.
Noriaki Iwase, et al. Substituted dihydropyrrolopyrazole derivative. US20190256531A1.