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 LY2109761

Description of LY2109761: LY2109761 is a novel transforming growth factor beta receptor type I and type II dual inhibitor. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT).  In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis. (source: Mol Cancer Ther. 2008 Apr;7(4):829-40.)

Current developer: Eli Lily.

1: Flechsig P, Dadrich M, Bickelhaupt S, Jenne J, Hauser K, Timke C, Peschke P, Hahn EW, Grone HJ, Yingling JM, Lahn MM, Wirkner U, Huber PE. LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP associated proinflammatory and proangiogenic signals. Clin Cancer Res. 2012 Apr 30. [Epub ahead of print] PubMed PMID: 22547771.

2: Wan X, Li ZG, Yingling JM, Yang J, Starbuck MW, Ravoori MK, Kundra V, Vazquez E, Navone NM. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth. Bone. 2012 Mar;50(3):695-703. Epub 2011 Dec 7. PubMed PMID: 22173053; PubMed Central PMCID: PMC3278589.

3: Bouquet F, Pal A, Pilones KA, Demaria S, Hann B, Akhurst RJ, Babb JS, Lonning SM, DeWyngaert JK, Formenti SC, Barcellos-Hoff MH. TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 2011 Nov 1;17(21):6754-65. Epub 2011 Oct 25. PubMed PMID: 22028490.

4: Zhang M, Kleber S, Röhrich M, Timke C, Han N, Tuettenberg J, Martin-Villalba A, Debus J, Peschke P, Wirkner U, Lahn M, Huber PE. Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 2011 Dec 1;71(23):7155-67. Epub 2011 Oct 17. PubMed PMID: 22006998.

5: Zhang M, Herion TW, Timke C, Han N, Hauser K, Weber KJ, Peschke P, Wirkner U, Lahn M, Huber PE. Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-β receptor I kinase inhibitor LY2109761. Neoplasia. 2011 Jun;13(6):537-49. PubMed PMID: 21677877; PubMed Central PMCID: PMC3114247.

6: Connolly EC, Saunier EF, Quigley D, Luu MT, De Sapio A, Hann B, Yingling JM, Akhurst RJ. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761. Cancer Res. 2011 Mar 15;71(6):2339-49. Epub 2011 Jan 31. PubMed PMID: 21282335; PubMed Central PMCID: PMC3059399.

7: Fransvea E, Mazzocca A, Santamato A, Azzariti A, Antonaci S, Giannelli G. Kinase activation profile associated with TGF-β-dependent migration of HCC cells: a preclinical study. Cancer Chemother Pharmacol. 2011 Jul;68(1):79-86. Epub 2010 Sep 16. PubMed PMID: 20844878.

8: Bauer JA, Ye F, Marshall CB, Lehmann BD, Pendleton CS, Shyr Y, Arteaga CL, Pietenpol JA. RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells. Breast Cancer Res. 2010;12(3):R41. Epub 2010 Jun 24. PubMed PMID: 20576088; PubMed Central PMCID: PMC2917036.

9: Ganapathy V, Ge R, Grazioli A, Xie W, Banach-Petrosky W, Kang Y, Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, Reiss M. Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer. 2010 May 26;9:122. PubMed PMID: 20504320; PubMed Central PMCID: PMC2890606.

10: Wang SE, Yu Y, Criswell TL, Debusk LM, Lin PC, Zent R, Johnson DH, Ren X, Arteaga CL. Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. Oncogene. 2010 Jun 10;29(23):3335-48. Epub 2010 Apr 12. PubMed PMID: 20383197; PubMed Central PMCID: PMC2883631.

11: Classen S, Muth C, Debey-Pascher S, Eggle D, Beyer M, Mallmann MR, Rudlowski C, Zander T, Pölcher M, Kuhn W, Lahn M, Schultze JL, Staratschek-Jox A. Application of T cell-based transcriptomics to identify three candidate biomarkers for monitoring anti-TGFbetaR therapy. Pharmacogenet Genomics. 2010 Mar;20(3):147-56. PubMed PMID: 20084050.

12: Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL, Datta PK. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010 Mar;138(3):969-80.e1-3. Epub 2009 Nov 10. PubMed PMID: 19909744; PubMed Central PMCID: PMC2831103.

13: Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S, Giannelli G. Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. Hepatology. 2010 Feb;51(2):523-34. PubMed PMID: 19821534.

14: Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology. 2009 Oct;50(4):1140-51. PubMed PMID: 19711426.

15: Zhang B, Halder SK, Zhang S, Datta PK. Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett. 2009 May 8;277(1):114-20. Epub 2009 Jan 14. PubMed PMID: 19147275; PubMed Central PMCID: PMC2776056.

16: Fransvea E, Mazzocca A, Antonaci S, Giannelli G. Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology. 2009 Mar;49(3):839-50. PubMed PMID: 19115199.

17: Xu Y, Tabe Y, Jin L, Watt J, McQueen T, Ohsaka A, Andreeff M, Konopleva M. TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. Br J Haematol. 2008 Jun;142(2):192-201. Epub 2008 May 19. PubMed PMID: 18492113.

18: Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008 Apr;7(4):829-40. PubMed PMID: 18413796; PubMed Central PMCID: PMC3088432.

19: Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology. 2008 May;47(5):1557-66. PubMed PMID: 18318443.

20: Li HY, McMillen WT, Heap CR, McCann DJ, Yan L, Campbell RM, Mundla SR, King CH, Dierks EA, Anderson BD, Britt KS, Huss KL, Voss MD, Wang Y, Clawson DK, Yingling JM, Sawyer JS. Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem. 2008 Apr 10;51(7):2302-6. Epub 2008 Mar 4. PubMed PMID: 18314943.

21: Lacher MD, Tiirikainen MI, Saunier EF, Christian C, Anders M, Oft M, Balmain A, Akhurst RJ, Korn WM. Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition. Cancer Res. 2006 Feb 1;66(3):1648-57. PubMed PMID: 16452224.