Abemaciclib inhibits kinases involved in transcriptional regulation

November 18, 2021

left: Prof. Matthias Geyer; right: Ines Kaltheuner (picture: David Fußhöller/University Clinics Bonn)

 

Protein structures of Homeodomain-interacting protein kinase (HIPK) and dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) reveals abemaciclib as potent inhibitor

 

Abemaciclib is a widely used drug in the therapy of hormone-receptor positive (HR-positive) and human epidermal growth factor receptor negative (HER2-negative) advanced breast cancer. The drug functions as a direct inhibitor of cyclin-dependent kinases 4 and 6 (Cdk4/Cdk6). Both kinases are responsible for the deactivation of retinoblastoma protein (Rb) by phosphorylation. Until its deactivation, Rb prevents cell cycle progression. The defective functionality of Rb in several major cancers leads to extensive cell growth and tumor progression. Direct targeting and inactivation of Cdk4/Cdk6 by abemaciclib prevents Rb deactivation and reduces therefore oncogenic cell proliferation.

 

 

Prof. Matthias Geyer, Director of the Institute of Structural Biology and member of the Cluster of Excellence ImmunoSensation2 at the University Clinics Bonn, and his team now show that abemaciclib also acts as potent inhibitor of further kinases involved in transcriptional regulation. In collaboration with the team of Prof. Nathanael Gray from the Dana-Farber Cancer Institute at Harvard Medical School, Boston, the scientists found Homeodomain-interacting protein kinases (HIPKs) and dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) to be inhibitable by abemaciclib. Both proteins are auto-activated and supposed to directly act in transcriptional regulation, as recombinant HIPKs and DYRK1A phosphorylate the negative elongation factor SPT5, the transcription factor c-Myc, and the C-terminal domain of RNA polymerase II.

 

By providing crystal structures of HIPK3 and DYRK1A bound to abemaciclib respectively, Prof. Geyer and his team show that abemaciclib-binding occurs to the hinge region of the kinases. Hence, the interaction occurs in a similar mode as previously observed for Cdk4 and Cdk6. “HIPKs and DYRK1A are closely related kinases and both are targeted by abemaciclib with similar efficacy as Cdk4/6.” Prof. Geyer states.

Like Cdk4 and Cdk6, HIPKs are involved in the pathologies of various cancers, but also other conditions like diabetes type II, chronic fibrosis, Alzheimer´s and Huntington´s disease. The crystal structures of HIPK3 and DYRK1A in complex with abemaciclib provided now, add to the understanding of the mode of action of the clinically used inhibitor. “Also, this work opens up new opportunities for the structure-guided design of small-molecule compounds targeting HIPKs” adds Ines Kaltheuner, PhD Student at the Institute of Structural Biology.

 

Participating institutions and funding:

Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.

This work was supported by a grant of the DFG (GE 976/9-2) and by a grant from the Deutsche Krebshilfe (70114008).

 

Publication:

Ines H. Kaltheuner et al. (2021). Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation. Nature Communications 12:6607. https://www.nature.com/articles/s41467-021-26935-z

 

 

Contact:

Prof. Matthias Geyer

Institute of Structural Biology
Biomedical Center
University of Bonn
Venusberg-Campus 1
53127 Bonn, Germany
phone: +49 228 287-51400
fax: +49 228 287-51221
e-mail: matthias.geyer(at)uni-bonn.de