Background:

THZ2 is a potent and selective CDK7 inhibitor (IC50=13.9 nM).

Cyclin-dependent kinase (CDK) is a group of serine/threonine kinases. It is activated by binding to cyclin and participates in the regulation of cell cycle.

THZ2 selectively targets CDK7 and potently blocks the proliferation of triple-negative breast cancer (TNBC) cells and induces apoptotic cell death without causing alteration in cell cycle. The low nanomolar dose of THZ2 also inhibits the clonogenic growth of TNBC cells with IC50 of 10 nM.

THZ2 is well tolerant in mice as 10 mg/kg intraperitoneal treatment of THZ2 twice daily does not cause weight loss or behavioral changes. THZ2 treatment also significantly reduces the tumor growth rate mice. In addition, both acute (50 hr) or chronic (25 days) exposure to THZ markedly decreases CTD phosphorylation of RNAPII at all three phosphorylation sites as indication of CDk7 being efficiently targeted.

Reference:
1.  Wang Y, Zhang T, Kwiatkowski N et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell. 2015 Sep 24;163(1):174-86.