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Volasertib

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Volasertib
Clinical data
Routes of
administration		Oral and Intravenous
Identifiers
  • N-((1S,4S)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-4-(((R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxybenzamide
CAS Number
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.246.197 Edit this at Wikidata
Chemical and physical data
FormulaC34H50N8O3
Molar mass618.827 g·mol−1
3D model (JSmol)
  • CC[C@H]1N(c2nc(ncc2N(C1=O)C)Nc3c(cc(cc3)C(=O)N[C@H]4CC[C@@H](CC4)N5CCN(CC5)CC6CC6)OC)C(C)C
  • InChI=1S/C34H50N8O3/c1-6-28-33(44)39(4)29-20-35-34(38-31(29)42(28)22(2)3)37-27-14-9-24(19-30(27)45-5)32(43)36-25-10-12-26(13-11-25)41-17-15-40(16-18-41)21-23-7-8-23/h9,14,19-20,22-23,25-26,28H,6-8,10-13,15-18,21H2,1-5H3,(H,36,43)(H,35,37,38)/t25-,26-,28-/m1/s1 ☒N
  • Key:SXNJFOWDRLKDSF-STROYTFGSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Volasertib (also known as BI 6727) is an experimental small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.[1]

Volasertib was awarded breakthrough drug status in September 2013[2] and orphan drug status for acute myeloid leukemia in April 2014.[3]

Mechanism of action

Volasertib is a novel small-molecule targeted therapy that blocks cell division by competitively binding to the ATP-binding pocket of the PLK1 protein. PLK1 proteins are found in the nuclei of all dividing cells and control multiple stages of the cell cycle and cell division.[4] [5] [6] The levels of the PLK1 protein are tightly controlled and are raised in normal cells that are dividing. Raised levels of the PLK1 protein are also found in many cancers including; breast, non-small cell lung, colorectal, prostate, pancreatic, papillary thyroid, ovarian, head and neck and Non-Hodgkin’s Lymphoma.[5] [6] [7] [8] [9] [10] Raised levels of PLK1 increase the probability of improper segregation of chromosomes which is a critical stage in the development of many cancers. Raised levels of PLK1 have been associated with a poorer prognosis and overall survival in some cancers[6][11] [12] In addition to its role in cell division, there is evidence that PLK1 also interacts with components of other pathways involved in cancer development including the K-Ras oncogene and the retinoblastoma and p53 tumour suppressors[13] These observations have led to PLK1 being recognised as an important target in the treatment of cancer.[citation needed]

Volasertib can be taken either orally or via intravenous infusion, once circulating in the blood stream it is distributed throughout the body, crosses the cell membrane and enters the nucleus of cells where it binds to its target; PLK1. Volasertib inhibits PLK1 preventing its roles in the cell-cycle and cell division which leads to cell arrest and programmed cell death.[4] Volasertib binds to and inhibits PLK1 at nanomolar doses however, it has also been shown to inhibit other PLK family members; PLK2 and PLK3 at higher; micromolar doses. The roles of PLK2 and PLK3 are less well understood; however they are known to be active during the cell cycle and cell division.[14]

Volasertib inhibits PLK1 in both cancer and normal cells; however it only causes irreversible inhibition and cell death in cancer cells, because inhibition of PLK1 in cancer cells arrests the cell cycle at a different point to normal, non-cancer cells. In cancer cells PLK1 inhibition results in G2/M cell cycle arrest followed by programmed cell death, however, in normal cells inhibition of PLK1 only causes temporary, reversible G1 and G2 arrest without programmed cell death.[15] This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.

Adverse effects

One of the undesirable effects of small-molecule drugs is that they can lack specificity for their target; hence bind to similar targets in other unrelated proteins, which can result in undesirable drug-related side effects. However, pre-clinical studies have shown volasertib binds in a highly selective manner to the kinase domain of the PLK family, without binding to other proteins with a kinase domain. Clinical studies have shown that at the maximum tolerated dose, side effects of volasertib include; anaemia (22%), thrombocytopenia, neutropenia and febrile neutropenia.[16] Common side effects as seen with other antimitotic agents such as vinca alkaloids and taxanes which include neuropathy, have not been observed with volasertib.

Studies

Preclinical studies on volasertib have demonstrated that it is highly effective at binding to and blocking PLK1 function and causing programmed cell death in colon and non-small cell lung cancer cells both in vitro and in vivo. Volasertib can also cause cell death in cancer cells that have are no longer sensitive to existing anti-mitotic drugs such as vinca alkaloids and taxanes.[15] This suggests that volasertib may be effective when used as a second line treatment in patients who have developed resistance to vinca alkaloid and taxane chemotherapeutics.[citation needed]

A first in man trial of volasertib in 65 patients with solid cancers reported that the drug is safe to administer to patients and is stable in the bloodstream. This study also reported favourable anti-cancer activity of the drug; three patients achieved a partial response, 48% of patients achieved stable disease and 6 patients achieved progression free survival of greater than 6 months.[16] A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukemia reported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.[17]

Clinical trials

Volasertib is currently undergoing investigation in phase I and II trials and has yet to be licensed by the FDA. Volasertib may be effective in several malignancies evidenced by the fact that its target PLK1 is overexpressed in up to 80% of malignancies, where it has been associated with a poorer treatment outcome and reduced overall survival.[1][6][11] Further phase 1 and 2 trials are active, investigating the effects of Volasertib both as a single agent and in combination with other agents in solid tumors and hematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia, lymphomas, myelodysplastic syndromes, and non-small call lung cancer.[18][3]

As of January 2017 it is in one phase III trial (for AML in over 65s), due to complete in February 2017.[19]

References

  1. ^ a b Schöffski P (June 2009). "Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology". The Oncologist. 14 (6): 559–70. doi:10.1634/theoncologist.2009-0010. PMID 19474163.
  2. ^ "Volasertib* receives FDA Breakthrough Therapy designation for treatment of patients with acute myeloid leukaemia". Boehringer Ingelheim. 17 September 2013. Archived from the original on 4 February 2017.
  3. ^ a b "Volasertib - Boehringer Ingelheim". AdisInsight. Springer Nature Switzerland AG.
  4. ^ a b Barr FA, Silljé HH, Nigg EA (June 2004). "Polo-like kinases and the orchestration of cell division". Nature Reviews. Molecular Cell Biology. 5 (6): 429–40. doi:10.1038/nrm1401. PMID 15173822. S2CID 7093201.
  5. ^ a b Garland LL, Taylor C, Pilkington DL, Cohen JL, Von Hoff DD (September 2006). "A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors". Clinical Cancer Research. 12 (17): 5182–9. doi:10.1158/1078-0432.ccr-06-0214. PMID 16951237.
  6. ^ a b c d Santamaria A, Neef R, Eberspächer U, Eis K, Husemann M, Mumberg D, et al. (October 2007). "Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis". Molecular Biology of the Cell. 18 (10): 4024–36. doi:10.1091/mbc.E07-05-0517. PMC 1995727. PMID 17671160.
  7. ^ Fisher RA, Ferris DK (2002). "The functions of Polo-like kinases and their relevance to human disease". Curr Med Chem. 2 (2): 125–134. doi:10.2174/1568013023358906.
  8. ^ Holtrich U, Wolf G, Bräuninger A, Karn T, Böhme B, Rübsamen-Waigmann H, Strebhardt K (March 1994). "Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors". Proceedings of the National Academy of Sciences of the United States of America. 91 (5): 1736–40. Bibcode:1994PNAS...91.1736H. doi:10.1073/pnas.91.5.1736. PMC 43238. PMID 8127874.
  9. ^ Steegmaier M, Hoffmann M, Baum A, Lénárt P, Petronczki M, Krssák M, et al. (February 2007). "BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo". Current Biology. 17 (4): 316–22. doi:10.1016/j.cub.2006.12.037. hdl:21.11116/0000-0002-1033-2. PMID 17291758. S2CID 14953248.
  10. ^ Winkles JA, Alberts GF (January 2005). "Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues". Oncogene. 24 (2): 260–6. doi:10.1038/sj.onc.1208219. PMID 15640841.
  11. ^ a b Eckerdt F, Yuan J, Strebhardt K (January 2005). "Polo-like kinases and oncogenesis". Oncogene. 24 (2): 267–76. doi:10.1038/sj.onc.1208273. PMID 15640842.
  12. ^ Weichert W, Ullrich A, Schmidt M, Gekeler V, Noske A, Niesporek S, et al. (April 2006). "Expression patterns of polo-like kinase 1 in human gastric cancer". Cancer Science. 97 (4): 271–6. doi:10.1111/j.1349-7006.2006.00170.x. PMID 16630118.
  13. ^ Liu X, Erikson RL (May 2003). "Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 100 (10): 5789–94. Bibcode:2003PNAS..100.5789L. doi:10.1073/pnas.1031523100. PMC 156279. PMID 12732729.
  14. ^ Schmit TL, Ahmad N (July 2007). "Regulation of mitosis via mitotic kinases: new opportunities for cancer management". Molecular Cancer Therapeutics. 6 (7): 1920–31. doi:10.1158/1535-7163.mct-06-0781. PMID 17620424.
  15. ^ a b Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. (May 2009). "BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity". Clinical Cancer Research. 15 (9): 3094–102. doi:10.1158/1078-0432.ccr-08-2445. PMID 19383823.
  16. ^ a b Gil T, Schoffski P, Awada A, Dumez H, Bartholomeus S, Selleslach J, et al. (May 2010). "Final analysis of a phase I single dose-escalation study of the novel polo-like kinase 1 inhibitor BI 6727 in patients with advanced solid tumors". Journal of Clinical Oncology. 20 (28, 15_suppl): 3061. doi:10.1200/jco.2010.28.15_suppl.3061.
  17. ^ Bug G, Schlenk RF, Müller-Tidow C, Lübbert M, Krämer A, Fleischer F, et al. (November 2010). "Phase I/II study of BI 6727 (volasertib), an intravenous polo-like kinase-1 (Plk1) inhibitor, in patients with acute myeloid leukemia (AML): results of the dose finding for BI 6727 in combination with low-dose cytarabine". Blood. 116 (21): Abstract 3316. doi:10.1182/blood.V116.21.3316.3316.
  18. ^ "Clinical Trials.gov Search of: Volasertib". ClinicalTrials.gov. 2011.
  19. ^ Clinical trial number NCT01721876 for "Volasertib in Combination With Low-dose Cytarabine in Patients Aged 65 Years and Above With Previously Untreated Acute Myeloid Leukemia, Who Are Ineligible for Intensive Remission Induction Therapy (POLO-AML-2)" at ClinicalTrials.gov
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