THZ1

THZ1 is a selective and potent covalent CDK7 inhibitor with an IC₅₀ of 3.2 nM. THZ1 also inhibits the closely related kinases CDK12 and CDK13 and downregulates MYC expression^[1][2]. IC50 & Target: IC50: 3.2 nM (CDK7)^[1] In Vitro: THZ1 inhibits Jurkat cell and Loucy cell with IC₅₀ of 50 nM, and 0.55 nM, respectively. THZ1 (9, 27, 83, 250, 750, and 2500 nM) inhibits CDK12 but at higher concentrations compared to CDK7. THZ1 (1 μM) irreversibly inhibits RNAPII CTD and CAK phosphorylation. THZ1 (2.5 µM) irreversibly inhibits RNAPII CTD phosphorylation by covalently targeting a unique cysteine located outside the kinase domain of CDK7 in Hela S3 cells. THZ1 (250 nM) causes decreased cellular proliferation and an increase in apoptotic index with concomitant reduction in anti-apoptotic proteins, most notably MCL-1 and XIAP in T-ALL cell lines^[1].
All genotypically-distinct human (hSCLC) cell lines exhibit high sensitivity to THZ1, with an IC₅₀ in the range of 5-20 nM^[3]. In Vivo: THZ1 (10 mg/kg) demonstrates potent killing of primary chronic lymphocytic leukemia (CLL) cells and anti-proliferative activity against primary TALL cells and in vivo against a human T-ALL xenograft^[1].
THZ1 (10 mg/kg, i.v.) inhibits tumor growth in a mouse model of human MYCN-amplified NB and shows no toxicity^[4].
THZ1 (10 mg/kg, i.p.) completely suppresses oesophageal squamous cell carcinoma tumour growth in vivo without loss of body weight or other common toxic effects^[5].