THZ1

THZ1 is a selective, potent, and covalent small molecule inhibitor of cyclin-dependent kinase 7 (CDK7), with an IC50 of approximately 3.2 nM for CDK7 inhibition[1][3][9]. It also inhibits the closely related kinases CDK12 and CDK13 at higher concentrations[3]. THZ1 acts by covalently binding to a cysteine residue outside the canonical kinase domain of CDK7, leading to irreversible inhibition[2][4]. Mechanistically, it blocks phosphorylation of the C-terminal domain (CTD) of RNA polymerase II, thereby disrupting transcriptional regulation and cell cycle progression. This results in downregulation of oncogenic transcription factors such as c-MYC and anti-apoptotic proteins like MCL-1 and BCL-xL[5][6]. THZ1 has demonstrated broad antiproliferative activity across various cancer cell lines—including T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), multiple myeloma, peripheral T-cell lymphoma, pancreatic ductal adenocarcinoma with KRAS-G12V mutation—and induces apoptosis via p53 upregulation or caspase activation in some contexts[5][6][8]. It is primarily used as a research tool compound; clinical development status for human use remains preclinical.

Other names

(E)-N-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide