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Volasertib (BI-6727)

Volasertib (BI-6727) is a dihydropteridinone Polo-like kinase 1 (Plk1) inhibitor with potential antineoplastic activity. Polo-like kinase 1 inhibitor BI 6727 selectively inhibits Plk1, inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells. Plk1, named after the polo gene of Drosophila melanogaster, is a serine/threonine protein kinase involved in regulating mitotic spindle function in a non-ATP competitive manner. BI 6727 is highly potent (enzyme IC(50) = 0.87 nmol/L, EC(50) = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Boehringer Ingelheim.

Phase I study of Volasertib: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400mg; however, 300mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000l), moderate clearance and a long half-life (~111h). CONCLUSION: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing. (source: Eur J Cancer. 2012 Jan;48(2):179-86)

1: Sanhaji M, Kreis NN, Zimmer B, Berg T, Louwen F, Yuan J. p53 is not directly relevant to the response of Polo-like kinase 1 inhibitors. Cell Cycle. 2012 Feb 1;11(3). [Epub ahead of print] PubMed PMID: 22262171.

2: Schöffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, Taton M, Fritsch H, Glomb P, Munzert G. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer. 2012 Jan;48(2):179-86. Epub 2011 Nov 24. PubMed PMID: 22119200.

3: Grinshtein N, Datti A, Fujitani M, Uehling D, Prakesch M, Isaac M, Irwin MS, Wrana JL, Al-Awar R, Kaplan DR. Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. Cancer Res. 2011 Feb 15;71(4):1385-95. Epub 2011 Feb 8. PubMed PMID: 21303981.

4: Schöffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009 Jun;14(6):559-70. Epub 2009 May 27. Review. PubMed PMID: 19474163.

5: Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009 May 1;15(9):3094-102. Epub 2009 Apr 21. PubMed PMID: 19383823.