New Drug Approvals

Home » Breakthrough Therapy Designation » US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML

US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML



Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 


Recent Posts

Blog Stats

  • 3,341,619 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,605 other followers

add to any




1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-


Ingelheim, Germany
Thursday, September 19, 2013, 16:00 Hrs  [IST]

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to Boehringer Ingelheim’s  volasertib, a selective and potent polo-like kinase (Plk) inhibitor, for the treatment of patients with acute myeloid leukaemia (AML), a type of blood cancer.

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

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.[2] [3] [4] 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] [3] [6] [4] [7] [8] 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[4][9] [10] 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[11] These observations have led to PLK1 being recognised as an important target in the treatment of cancer.

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.[2] 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.[12]

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.[13] This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.

Clinical uses

Volasertib is currently undergoing investigation in phase 1 and 2 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][4][9]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 tumours and haematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia.[14]


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.[13] 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.

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.[15] A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukaemiareported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.[16]

  1.  Schoffski, P. (2009). “Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology”. Oncologist 14 (6): 559–70. ISSN (Electronic) 1083-7159 (Linking) 1549-490X (Electronic) 1083-7159 (Linking).
  2.  Barr, F. A.; H. H. Sillje, E. A. Nigg (2004). “Polo-like kinases and the orchestration of cell division”. Nat Rev Mol Cell Biol 5 (6): 429–40. ISSN (Print) 1471-0072 (Linking) 1471-0072 (Print) 1471-0072 (Linking).
  3.  Garland, L. L.; C. Taylor, D. L. Pilkington, J. L. Cohen, D. D. Von Hoff (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”. Clin Cancer Res 12 (17): 5182–9. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
  4.  Santamaria, A.; R. Neef, U. Eberspacher, K. Eis, M. Husemann, D. Mumberg, S. Prechtl, V. Schulze, G. Siemeister, L. Wortmann, F. A. Barr, E. A. Nigg (2007). “Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis”. Mol Biol Cell 18 (10): 4024–36. ISSN (Print) 1059-1524 (Linking) 1059-1524 (Print) 1059-1524 (Linking).
  5. Fisher, R.A.H.; D.K. Ferris (2002). “The functions of Polo-like kinases and their relevance to human disease.”. Curr Med Chem 2: 125–134.
  6.  Holtrich, U.; G. Wolf, A. Brauninger, T. Karn, B. Bohme, H. Rubsamen-Waigmann, K. Strebhardt (1994). “Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors”Proc Natl Acad Sci U S A 91 (5): 1736–40. doi:10.1073/pnas.91.5.1736ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking)PMC 43238PMID 8127874.
  7.  Steegmaier, M.; M. Hoffmann, A. Baum, P. Lenart, M. Petronczki, M. Krssak, U. Gurtler, P. Garin-Chesa, S. Lieb, J. Quant, M. Grauert, G. R. Adolf, N. Kraut, J. M. Peters, W. J. Rettig (2007). “BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo”. Curr Biol 17 (4): 316–22. doi:10.1016/j.cub.2006.12.037ISSN (Print) 0960-9822 (Linking) 0960-9822 (Print) 0960-9822 (Linking)PMID 17291758.
  8.  Winkles, J. A.; G. F. Alberts (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.1208219ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking)PMID 15640841.
  9.  Eckerdt, F.; J. Yuan, K. Strebhardt (2005). “Polo-like kinases and oncogenesis”. Oncogene 24 (2): 267–76. doi:10.1038/sj.onc.1208273ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking)PMID 15640842.
  10.  Weichert, W.; A. Ullrich, M. Schmidt, V. Gekeler, A. Noske, S. Niesporek, A. C. Buckendahl, M. Dietel, C. Denkert (2006). “Expression patterns of polo-like kinase 1 in human gastric cancer”. Cancer Sci 97 (4): 271–6. ISSN (Print) 1347-9032 (Linking) 1347-9032 (Print) 1347-9032 (Linking).
  11.  Liu, X.; R. L. Erikson (2003). “Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells”Proc Natl Acad Sci U S A 100 (10): 5789–94. doi:10.1073/pnas.1031523100.ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking)PMC 156279PMID 12732729.
  12.  Schmit, T. L.; N. Ahmad (2007). “Regulation of mitosis via mitotic kinases: new opportunities for cancer management”. Mol Cancer Ther 6 (7): 1920–31. ISSN (Print) 1535-7163 (Linking) 1535-7163 (Print) 1535-7163 (Linking).
  13.  Rudolph, D.; M. Steegmaier, M. Hoffmann, M. Grauert, A. Baum, J. Quant, C. Haslinger, P. Garin-Chesa, G. R. Adolf (2009). “BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity”. Clin Cancer Res 15 (9): 3094–102. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
  14. (2011). “Clinical Search of: Volasertib”. Missing or empty |url= (help)
  15.  Gil, T.; P. Schöffski, A. Awada, H. Dumez, S. Bartholomeus, J. Selleslach, M. Taton, H. Fritsch, P. Glomb, Munzert G.M. (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”J Clin Oncol 28.
  16. Bug, G.; R. F. Schlenk, C. Müller-Tidow, M. Lübbert, A. Krämer, F. Fleischer, T. Taube, O. G. Ottmann, H. Doehner (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”. 52nd ASH Annual Meeting and Exposition. Orange County Convention Centre, Florida: American Society of Haematology.


1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
methoxy-, hydrochloride (1:3)
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-


SPONSOR Boehringer Ingelheim Pharmaceuticals, Inc.

Volasertib is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1), a key regulator of cell-cycle progression. Volasertib is a dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for combination therapy of advanced and/or metastatic solid tumours.

Volasertib (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,

Figure US20130122111A1-20130516-C00001

This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.

U.S. 8,188,086

Several dihydropteridione derivatives effectively prevent cell proliferation. G. Linz and co-inventors report a comprehensive method for preparing pharmacologically active crystalline and anhydrous forms of compound 1 (Figure 1) that are suitable for drug formulations.

The inventors list several criteria for the properties of 1 and its manufacturing procedure:

  • favorable bulk characteristics such as drying times, filterability, solubility in biologically acceptable solvents, and thermal stability;
  • purity of the pharmaceutical composition;
  • low hygroscopicity;
  • no or low tendency toward polymorphism; and
  • scalability to a convenient commercial process.

They describe their finding that the tri-HCl salt of 1 satisfies these criteria as “surprising”.

Free base 1 is prepared by condensing cyclopropylmethylpiperazine derivative 2 with pteridinone 3 in the presence of p-toluenesulfonic acid (TsOH), as shown in Figure 1. After the reaction is complete, the crude free base 1 is recovered as a viscous oil. It is then treated with HCl in an organic solvent to form 3HCl, isolated in 91% yield. Alternatively, the free base is not isolated; instead, concd HCl is added to the reaction mixture, followed by acetone. The crude salt is recovered in 92% yield.

The salt is purified by crystallization from refluxing EtOH, adding water, and cooling to precipitate the crystals. The inventors do not report the purity of this or any other reaction product.

The inventors obtained a hydrated form of the tri-HCl salt by dissolving the free base in EtOH at room temperature, followed by adding concd HCl and cooling to 2 °C. An anhydrous form can be recovered by drying the hydrate at 130 °C. The solubility of the hydrated salt in aqueous and organic media is reported, as are X-ray diffraction data for the hydrated form. The hydrated salt has good solid-state stability.

The patent also contains the syntheses of reactants 2 and 3 (Figures 2 and 3). The preparation of 2 begins with the formation of amide 7. Acid 4 is treated with SOCl2–DMF to form acid chloride 5; the crude product is added to a suspension of chiral difunctionalized cyclohexane 6 in THF and aq K2CO3 to produce 7. The crude product is recovered in 98% yield and oxidized to 8 with RuCl3 and N-methylmorpholine N-oxide (NMMO) in 91% yield.

Amide 8 reacts with cyclopropylmethylpiperazine 9 in the presence of methanesulfonic acid (MsOH). The solvent is evaporated, and the reaction mixture is treated with NaBH4. After further workup, product 10 is isolated in 46% yield. The nitro group is then hydrogenated over Raney Ni to give 2 in 90% yield. An alternative method for preparing10 is also described.

To prepare 3, readily available amino acid 11 is esterified and alkylated to form 12. In a multistep, one-pot procedure, 11 is first treated with HC(OMe)3 and SOCl2. Further reaction with NaBH(OAc)3, acetone, and NH4OH produces 12 as its HCl salt in 90% yield. The salt is treated with aq NaOH to form the free base, which reacts with pyrimidine 13 in the presence of NaHCO3 to form 14 in 79% isolated yield.

The pteridinone system is formed by hydrogenating 14 over a Pt/C catalyst in the presence of V(acac)3. Precursor 15 is recovered in 90% yield and methylated with (MeO)2CO and K2CO3 to give 3 in 82% isolated yield.

The inventors succeeded in developing a route for making a crystalline salt that is suitable for preparing pharmaceutical formulations. The many synthetic steps, however, use a large number of solvents that are frequently evaporated to dryness. [This observation implies that the processes have a significant environmental burden. —Ed.] (Boehringer Ingelheim International [Ingelheim am Rhein, Germany]. US Patent U.S. 8,188,086,


Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.


Follow New Drug Approvals on

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,605 other followers



DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →



Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: