T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer. Although this disease can be well treated through intensive chemotherapy, it remains mostly fatal in patients who become resistant to chemotherapy or undergo relapse. Alternative therapeutic strategies are therefore needed to cure these patients.
By screening a library of kinase inhibitors, Nathanael Gray, Dana-Faber Cancer Institute, Boston, USA, and colleagues discovered THZ1 (pictured), a phenylaminopyrimidine which strongly reduced the proliferation of T-ALL cells. The new chemical covalently inhibits CDK7 (cyclin-dependent kinase 7), a protein kinase which controls cell proliferation and gene expression. THZ1 acts in a highly selective manner by targeting a cystein residue located outside of the CDK7 kinase domain.
By selectively inhibiting CDK7, THZ1 blocked leukemia development in animal models of the disease, thus demonstrating its potential as a novel drug for T-ALL patients.
- Targeting transcription regulation in cancer with a covalent CDK7 inhibitor,
Nicholas Kwiatkowski, Tinghu Zhang, Peter B. Rahl, Brian J. Abraham, Jessica Reddy, Scott B. Ficarro, Anahita Dastur, Arnaud Amzallag, Sridhar Ramaswamy, Bethany Tesar, Catherine E. Jenkins, Nancy M. Hannett, Douglas McMillin, Takaomi Sanda, Taebo Sim, Nam Doo Kim, Thomas Look, Constantine S. Mitsiades, Andrew P. Weng, Jennifer R. Brown, Cyril H. Benes, Jarrod A. Marto, Richard A. Young, Nathanael S. Gray,