Review
Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709

https://doi.org/10.1016/j.biopha.2006.06.003Get rights and content

Abstract

Loss of cell cycle control and tumor-induced neovascularization are major drivers of human tumor growth. The multi-target tumor growth inhibitor ZK 304709 is a nanomolar inhibitor of cyclin-dependent kinases 1, 2, 4, 7 and 9, as well as vascular endothelial growth factor receptor tyrosine kinase 1–3 and of platelet-derived growth factor receptor β tyrosine kinase. The multi-targeted mode of action of ZK 304709 acting on cell cycle and angiogenesis resulted in superior efficacy compared to standard chemotherapeutic compounds both in s.c. human tumor xenografts as well as orthotopic human pancreatic carcinoma models.

Introduction

The majority of human solid tumors especially those derived from the gastrointestinal tract, breast, and lung cannot be cured if metastases occurred. Chemotherapy, radiation therapy, antibody therapies and anti angiogenic therapy have a certain positive influence on survival, but there is plenty of room for clinical improvement.

This may be achieved by compounds having a novel mode of action. Here we present the novel development compound ZK 304709 having a mode of action different from standard chemotherapy and showing strong anti tumor efficacy in a variety of standard human xeno-transplantation models as well as orthotopic models for pancreatic carcinoma.

Section snippets

Results and discussion

ZK 304709 is a first-in-class, oral multi-target tumor growth inhibitor™ (MTGI™) that blocks tumor cell proliferation and induces apoptosis by inhibiting a unique combination of disease progression driving pathways. This is accomplished by potent inhibition of (a) serine/threonine kinases CDK 1, 2 and 4 leading to inhibition of cell cycle progression, (b) serine/threonine kinases CDK 7 and 9 leading to apoptosis in resting tumor cells, (c) receptor tyrosine kinases VEGF-R1, R2 and R3, and

Conclusion

The combined inhibition of cell cycle and angiogenesis by ZK 304709 resulted in superior efficacy compared to standard chemotherapeutic compounds both in s.c. human tumor xenografts as well as orthotopic human pancreatic carcinoma models. ZK 304709 is in Phase I clinical studies.

References (0)

Cited by (51)

  • Eco-friendly sequential one-pot synthesis, molecular docking, and anticancer evaluation of arylidene-hydrazinyl-thiazole derivatives as CDK2 inhibitors

    2021, Bioorganic Chemistry
    Citation Excerpt :

    III) Compounds with CDK-inhibitory activity and off-kinase targets, which can be exploited to enhance their anticancer activity. This class includes ZK-304709 (9, CDK/VEGFR activity) and JNJ-7706621 (10, CDK/Aurora A and B activity) (Fig. 2) [22–24]. Compound 7 is FDA approved in 2015 for treatment of breast cancer.

  • Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

    2015, Bioorganic and Medicinal Chemistry Letters
  • Targeting cell cycle regulation in cancer therapy

    2013, Pharmacology and Therapeutics
View all citing articles on Scopus
View full text