Design, synthesis, and biological activity of 1,2,3-triazolobenzodiazepine BET bromodomain inhibitors

Journal article

Sharp, Phillip P., Garnier, Jean-Marc, Hatfaludi, Tamas, Xu, Zhen, Segal, David, Jarman, Kate E., Jousset, Hélène, Garnham, Alexandra, Feutrill, John T., Cuzzupe, Anthony, Hall, Peter, Taylor, Scott, Walkley, Carl, Tyler, Dean, Dawson, Mark A., Czabotar, Peter, Wilks, Andrew F., Glaser, Stefan, Huang, David C. S. and Burns, Christopher J.. (2017). Design, synthesis, and biological activity of 1,2,3-triazolobenzodiazepine BET bromodomain inhibitors. ACS Medicinal Chemistry Letters. 8(12), pp. 1298-1303. https://doi.org/10.1021/acsmedchemlett.7b00389
AuthorsSharp, Phillip P., Garnier, Jean-Marc, Hatfaludi, Tamas, Xu, Zhen, Segal, David, Jarman, Kate E., Jousset, Hélène, Garnham, Alexandra, Feutrill, John T., Cuzzupe, Anthony, Hall, Peter, Taylor, Scott, Walkley, Carl, Tyler, Dean, Dawson, Mark A., Czabotar, Peter, Wilks, Andrew F., Glaser, Stefan, Huang, David C. S. and Burns, Christopher J.
Abstract

A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.

Keywordsbenzodiazepine; Bromodomain; JQ1; leukemia; triazole
Year2017
JournalACS Medicinal Chemistry Letters
Journal citation8 (12), pp. 1298-1303
PublisherAmerican Chemical Society
ISSN1948-5875
Digital Object Identifier (DOI)https://doi.org/10.1021/acsmedchemlett.7b00389
Scopus EID2-s2.0-85038387097
Open accessPublished as green open access
Page range1298-1303
Research GroupMary MacKillop Institute for Health Research
Author's accepted manuscript
File Access Level
Open
Publisher's version
License
All rights reserved
File Access Level
Controlled
Place of publicationUnited States of America
EditorsD. C. Liotta
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Green, Alanna C., Poulton, Ingrid J., Vrahnas, Christina, Häusler, Karl D., Walkley, Carl, Wu, Joy Y., Martin, T. John, Gillespie, Matthew T., Chandraratna, Roshantha A. S., Quinn, Julian M. W., Sims, Natalie A. and Purton, L. E.. (2015). RARγ is a negative regulator of osteoclastogenesis. The Journal of Steroid Biochemistry and Molecular Biology. 150, pp. 46 - 53. https://doi.org/10.1016/j.jsbmb.2015.03.005
Brief report: The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation
Martin, Sally K., Fitter, Stephen, Dutta, Ankit K., Matthews, Mary P., Walkley, Carl, Hall, Michael N., Ruegg, Markus A., Gronthos, Stan and Zannettino, Andrew C. W.. (2015). Brief report: The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem Cells. 33(4), pp. 1359 - 1365. https://doi.org/10.1002/stem.1931
Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure
Askmyr, Maria, White, Kirby E., Jovic, Tanja, King, Hannah A., Quach, Julie M., Maluenda, Ana C., Baker, E. K., Smeets, Monique F., Walkley, Carl and Purton, L. E.. (2015). Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure. Scientific Reports. 5, pp. 1 - 13. https://doi.org/10.1038/srep15529
PTHrP, its receptor, and protein kinase A activation in osteosarcoma
Walkley, Carl, Walia, Mannu K., Ho, P.W.M. and Martin, T. J.. (2014). PTHrP, its receptor, and protein kinase A activation in osteosarcoma. Molecular & Cellular Oncology. 1(4), pp. 1 - 3. https://doi.org/10.4161/23723548.2014.965624
Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms
Chalk, Alistair M., Liddicoat, Brian J., Walkley, Carl and Singbrant, Sofie. (2014). Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms. Genomics Data. 2, pp. 189 - 191. https://doi.org/10.1016/j.gdata.2014.06.022
The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
Singbrant, Sofie, Wall, Meaghan, Moody, Jennifer, Karlsson, Göran, Chalk, Alistair M., Liddicoat, Brian J., Russell, Megan R., Walkley, Carl R. and Karlsson, Stefan. (2014). The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease. Haematologica. 99(4), pp. 647 - 655. https://doi.org/10.3324/haematol.2013.093971
The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis
Smeets, Monique F., DeLuca, Elisabetta, Wall, Meaghan, Quach, Julie M., Chalk, Alistair M., Deans, Andrew J., Heierhorst, Jörg, Purton, Louise E., Izon, David J. and Walkley, Carl R.. (2014). The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis. Journal of Clinical Investigation. 124(8), pp. 3551 - 3565. https://doi.org/10.1172/JCI75334
Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells?
Mutsaers, Anthony J. and Walkley, Carl R.. (2014). Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells? Bone. 62, pp. 56 - 63. https://doi.org/10.1016/j.bone.2014.02.003
Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation
Kansara, Maya, Leong, Huei San, Lin, Dan Mei, Popkiss, Sophie, Pang, Puiyi, Garsed, Dale W., Walkley, Carl R., Cullinane, Carleen, Ellul, Jason, Haynes, Nicole M., Hicks, Rod, Kuijjer, Marieke L., Cleton-Jansen, Anne-Marie, Hinds, Philip W., Smyth, Mark J. and Thomas, David M.. (2013). Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation. Journal of Clinical Investigation. 123(12), pp. 5351 - 5360. https://doi.org/10.1172/JCI70559
Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors
Dewamitta, Sita R., Joseph, Chacko, Purton, Louise E. and Walkley, Carl R.. (2013). Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors. British Journal of Haematology. 164(2), pp. 280 - 285. https://doi.org/10.1111/bjh.12578
Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA
Mutsaers, Anthony J., Ng, Alvin J. M., Baker, Emma K., Russell, Megan R., Chalk, Alistair M., Wall, Meaghan, Liddicoat, Brian J. J., Ho, Patricia W. M., Slavin, John L., Goradia, Ankita, Martin, T. John, Purton, Louise E., Dickins, Ross A. and Walkley, Carl R.. (2013). Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA. Bone. 55(1), pp. 166 - 178. https://doi.org/10.1016/j.bone.2013.02.016
Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment
Dewamitta, Sita R., Russell, Megan R., Nandurkar, Harshal and Walkley, Carl R.. (2013). Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment. Haematologica. 98(5), pp. 686 - 690. https://doi.org/10.3324/haematol.2012.078709
Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies
Joseph, Chacko, Quach, Julie M., Walkley, Carl R., Lane, Steven W., Celso, Cristina Lo and Purton, Louise E.. (2013). Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell. 13(5), pp. 520 - 533. https://doi.org/10.1016/j.stem.2013.10.010
The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim
Jurado, Sabine, Gleeson, Kimberly, O’Donnell, Kristy, Izon, David J., Walkley, Carl R., Strasser, Andreas, Tarlinton, David M. and Heierhorst, Jörg. (2012). The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. Journal of Experimental Medicine. 209(9), pp. 1629-1639. https://doi.org/10.1084/jem.20120785
Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion
Lu, Jiayun, Sun, Yan, Nombela-Arrieta, Cesar, Du, Karrie P., Park, Shin-Young, Chai, Li, Walkley, Carl, Luo, Hongbo R. and Silberstein, Leslie E.. (2012). Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion. Experimental Hematology. 40(4), pp. 307-317. https://doi.org/10.1016/j.exphem.2011.11.010
Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment
Singbrant, Sofie, Russell, Megan R., Jovic, Tanja, Liddicoat, Brian, Izon, David J., Purton, Louise E., Sims, Natalie A., Martin, T. John, Sankaran, Vijay G. and Walkley, Carl R.. (2011). Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood. 117(21), pp. 5631-5642. https://doi.org/10.1182/blood-2010-11-320564
Erythropoiesis, anemia and the bone marrow microenvironment
Walkley, Carl R.. (2011). Erythropoiesis, anemia and the bone marrow microenvironment. International Journal of Hematology. 93, pp. 10-13. https://doi.org/10.1007/s12185-010-0759-6
Defining the hematopoietic stem cell niche : The chicken and the egg conundrum
Singbrant, Sofie, Askmyr, Maria, Purton, Louise E. and Walkley, Carl R.. (2011). Defining the hematopoietic stem cell niche : The chicken and the egg conundrum. Journal of Cellular Biochemistry. 112(6), pp. 1486-1490. https://doi.org/10.1002/jcb.23085
Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan, Schertzer, Jonathan, Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl, Izon, David, Honeyman, Jane, Chen, Zhi-Ping, Van Denderen, Bryce, Kemp, Bruce and Steinberg, Gregory. (2011). Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577
Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan D., Schertzer, Jonathan D., Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl R., Izon, David, Honeyman, Jane, Chen, Zhi-Ping, van Denderen, Bryce J., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2011). Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577