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MedKoo product information:

BI-2536

BI-2563 is a small molecule compound with potential antineoplastic activities. BI 2536 binds to and inhibits Polo-like kinase 1 (Plk1), resulting in mitotic arrest, disruption of cytokinesis, and apoptosis in susceptible tumor cell populations. Plk1, a serine/threonine-protein kinase, is a key regulator of multiple processes fundamental to mitosis and cell division. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Boehringer Ingelheim.

Phase I study of BI2536 in patients with advanced solid tumors. Forty-four and 26 patients received each treatment schedule, respectively. The MTD of BI 2536 in the day 1 and 8 schedule was 100 mg per administration (200 mg per course). The MTD for the second dosing schedule was not determined; a 225-mg dose was well tolerated. The most frequently reported treatment-related nonhematologic adverse events were gastrointestinal events and fatigue. Hematotoxicity as the most relevant side effect was similar in both schedules; neutropenia grades 3 and 4 were observed in 16 patients (36.4%) of the day 1 and 8 schedule and 13 patients (50%) of the 24-hour infusion. Fourteen patients (32%) treated in the day 1 and 8 dosing schedule had a best overall response of stable disease. Plasma concentrations of BI 2536 increased dose proportionally, with no relevant accumulation of exposure in the day 1 and 8 dosing schedule. The average terminal half-life was 50 hours. BI 2536 administered in either treatment schedule has adequate safety in patients with advanced solid tumors, warranting further clinical investigation of polo-like kinase-1 inhibitors. (source: Clin Cancer Res. 2010 Sep 15;16(18):4666-74).

BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma.  Cells treated with BI 2536 accumulate in the G(2)/M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells. Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Those data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma. (source: Exp Hematol. 2011 Mar;39(3):330-8)

1: Pezuk JA, Brassesco MS, Oliveira JC, Morales AG, Montaldi AP, Sakamoto-Hojo ET, Scrideli CA, Tone LG. Antiproliferative in vitro effects of BI 2536-mediated PLK1 inhibition on cervical adenocarcinoma cells. Clin Exp Med. 2011 Nov 12. [Epub ahead of print] PubMed PMID: 22080235.

2: Morales AG, Brassesco MS, Pezuk JA, Oliveira JC, Montaldi AP, Sakamoto-Hojo ET, Scrideli CA, Tone LG. BI 2536-mediated PLK1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity. Anticancer Drugs. 2011 Nov;22(10):995-1001. PubMed PMID: 21822121.

3: Soto E, Staab A, Doege C, Freiwald M, Munzert G, Trocóniz IF. Comparison of different semi-mechanistic models for chemotherapy-related neutropenia: application to BI 2536 a Plk-1 inhibitor. Cancer Chemother Pharmacol. 2011 Dec;68(6):1517-27. Epub 2011 Apr 24. PubMed PMID: 21516508.

4: Eckerdt F. Polo-like kinase 1 inhibitors SBE13 and BI 2536 induce different responses in primary cells. Cell Cycle. 2011 Apr 1;10(7):1027-8. Epub 2011 Apr 1. PubMed PMID: 21415595.

5: Peter B, Gleixner KV, Cerny-Reiterer S, Herrmann H, Winter V, Hadzijusufovic E, Ferenc V, Schuch K, Mirkina I, Horny HP, Pickl WF, Müllauer L, Willmann M, Valent P. Polo-like kinase-1 as a novel target in neoplastic mast cells: demonstration of growth-inhibitory effects of small interfering RNA and the Polo-like kinase-1 targeting drug BI 2536. Haematologica. 2011 May;96(5):672-80. Epub 2011 Jan 17. PubMed PMID: 21242189; PubMed Central PMCID: PMC3084913.

6: Stewart HJ, Kishikova L, Powell FL, Wheatley SP, Chevassut TJ. The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma. Exp Hematol. 2011 Mar;39(3):330-8. Epub 2010 Dec 22. PubMed PMID: 21184800.

7: Soto E, Staab A, Freiwald M, Munzert G, Fritsch H, Döge C, Trocóniz IF. Prediction of neutropenia-related effects of a new combination therapy with the anticancer drugs BI 2536 (a Plk1 inhibitor) and pemetrexed. Clin Pharmacol Ther. 2010 Nov;88(5):660-7. Epub 2010 Oct 6. PubMed PMID: 20927084.

8: Lu B, Mahmud H, Maass AH, Yu B, van Gilst WH, de Boer RA, Silljé HH. The Plk1 inhibitor BI 2536 temporarily arrests primary cardiac fibroblasts in mitosis and generates aneuploidy in vitro. PLoS One. 2010 Sep 24;5(9):e12963. PubMed PMID: 20886032; PubMed Central PMCID: PMC2945759.

9: Hofheinz RD, Al-Batran SE, Hochhaus A, Jäger E, Reichardt VL, Fritsch H, Trommeshauser D, Munzert G. An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin Cancer Res. 2010 Sep 15;16(18):4666-74. Epub 2010 Aug 3. PubMed PMID: 20682708.

10: Sebastian M, Reck M, Waller CF, Kortsik C, Frickhofen N, Schuler M, Fritsch H, Gaschler-Markefski B, Hanft G, Munzert G, von Pawel J. The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. J Thorac Oncol. 2010 Jul;5(7):1060-7. PubMed PMID: 20526206.

11: Schöffski P, Blay JY, De Greve J, Brain E, Machiels JP, Soria JC, Sleijfer S, Wolter P, Ray-Coquard I, Fontaine C, Munzert G, Fritsch H, Hanft G, Aerts C, Rapion J, Allgeier A, Bogaerts J, Lacombe D. Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI). Eur J Cancer. 2010 Aug;46(12):2206-15. Epub 2010 May 13. PubMed PMID: 20471824.

12: Gleixner KV, Ferenc V, Peter B, Gruze A, Meyer RA, Hadzijusufovic E, Cerny-Reiterer S, Mayerhofer M, Pickl WF, Sillaber C, Valent P. Polo-like kinase 1 (Plk1) as a novel drug target in chronic myeloid leukemia: overriding imatinib resistance with the Plk1 inhibitor BI 2536. Cancer Res. 2010 Feb 15;70(4):1513-23. Epub 2010 Feb 9. PubMed PMID: 20145140.

13: Wäsch R, Hasskarl J, Schnerch D, Lübbert M. BI_2536--targeting the mitotic kinase Polo-like kinase 1 (Plk1). Recent Results Cancer Res. 2010;184:215-8. Review. PubMed PMID: 20072841.

14: Soto E, Staab A, Tillmann C, Trommeshauser D, Fritsch H, Munzert G, Trocóniz IF. Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development. Cancer Chemother Pharmacol. 2010 Sep;66(4):785-95. Epub 2010 Jan 9. PubMed PMID: 20062994.

15: Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, Rouyrre N, Trommeshauser D, Hoesl CE, Munzert G. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2008 Dec 1;26(34):5511-7. Epub 2008 Oct 27. PubMed PMID: 18955456.

16: Lénárt P, Petronczki M, Steegmaier M, Di Fiore B, Lipp JJ, Hoffmann M, Rettig WJ, Kraut N, Peters JM. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007 Feb 20;17(4):304-15. Epub 2007 Feb 8. PubMed PMID: 17291761.

17: Steegmaier M, Hoffmann M, Baum A, Lénárt P, Petronczki M, Krssák M, Gürtler U, Garin-Chesa P, Lieb S, Quant J, Grauert M, Adolf GR, Kraut N, Peters JM, Rettig WJ. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007 Feb 20;17(4):316-22. Epub 2007 Feb 8. PubMed PMID: 17291758.