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Title: Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design

Abstract

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Furthermore, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]; ORCiD logo [1]
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  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health; Leidos Biomed Prime; NCI SPORE
OSTI Identifier:
1433690
Grant/Contract Number:  
AC02-06CH11357; 1S-10RR025677-01; HHSN261200800001E; P50CA098131
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 6; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; indoles; assays; inhibitors; amides; screening assays; structure-based design; Mcl-1 inhibitor; apoptosis; cancer; drug discovery

Citation Formats

Shaw, Subrata, Bian, Zhiguo, Zhao, Bin, Tarr, James C., Veerasamy, Nagarathanam, Jeon, Kyu Ok, Belmar, Johannes, Arnold, Allison L., Fogarty, Stuart A., Perry, Evan, Sensintaffar, John L., Camper, DeMarco V., Rossanese, Olivia W., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.7b01155.
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Shaw, Subrata, Bian, Zhiguo, Zhao, Bin, Tarr, James C., Veerasamy, Nagarathanam, Jeon, Kyu Ok, Belmar, Johannes, Arnold, Allison L., Fogarty, Stuart A., Perry, Evan, Sensintaffar, John L., Camper, DeMarco V., Rossanese, Olivia W., Lee, Taekyu, Olejniczak, Edward T., & Fesik, Stephen W. Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design. United States. https://doi.org/10.1021/acs.jmedchem.7b01155
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Shaw, Subrata, Bian, Zhiguo, Zhao, Bin, Tarr, James C., Veerasamy, Nagarathanam, Jeon, Kyu Ok, Belmar, Johannes, Arnold, Allison L., Fogarty, Stuart A., Perry, Evan, Sensintaffar, John L., Camper, DeMarco V., Rossanese, Olivia W., Lee, Taekyu, Olejniczak, Edward T., and Fesik, Stephen W. Thu . "Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design". United States. https://doi.org/10.1021/acs.jmedchem.7b01155. https://www.osti.gov/servlets/purl/1433690.
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@article{osti_1433690,
title = {Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design},
author = {Shaw, Subrata and Bian, Zhiguo and Zhao, Bin and Tarr, James C. and Veerasamy, Nagarathanam and Jeon, Kyu Ok and Belmar, Johannes and Arnold, Allison L. and Fogarty, Stuart A. and Perry, Evan and Sensintaffar, John L. and Camper, DeMarco V. and Rossanese, Olivia W. and Lee, Taekyu and Olejniczak, Edward T. and Fesik, Stephen W.},
abstractNote = {Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Furthermore, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.},
doi = {10.1021/acs.jmedchem.7b01155},
journal = {Journal of Medicinal Chemistry},
number = 6,
volume = 61,
place = {United States},
year = {Thu Jan 11 00:00:00 EST 2018},
month = {Thu Jan 11 00:00:00 EST 2018}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acs.jmedchem.7b01155
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Works referenced in this record:

The Bcl-2 apoptotic switch in cancer development and therapy
journal, February 2007

Cell Death
journal, January 2004

Targeting Apoptosis Pathways in Cancer Therapy
journal, May 2005

  • Ghobrial, I. M.; Witzig, T. E.; Adjei, A. A.
  • CA: A Cancer Journal for Clinicians, Vol. 55, Issue 3
  • DOI: 10.3322/canjclin.55.3.178

Bcl-2 and the regulation of programmed cell death
journal, January 1994

Bcl-2 inhibitors: small molecules with a big impact on cancer therapy
journal, September 2008

  • Vogler, M.; Dinsdale, D.; Dyer, M. J. S.
  • Cell Death & Differentiation, Vol. 16, Issue 3
  • DOI: 10.1038/cdd.2008.137

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
journal, December 2013

  • Czabotar, Peter E.; Lessene, Guillaume; Strasser, Andreas
  • Nature Reviews Molecular Cell Biology, Vol. 15, Issue 1
  • DOI: 10.1038/nrm3722

The Hallmarks of Cancer
journal, January 2000

The landscape of somatic copy-number alteration across human cancers
journal, February 2010

  • Beroukhim, Rameen; Mermel, Craig H.; Porter, Dale
  • Nature, Vol. 463, Issue 7283
  • DOI: 10.1038/nature08822

Chemical Genomics Identifies Small-Molecule MCL1 Repressors and BCL-xL as a Predictor of MCL1 Dependency
journal, April 2012

Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells
journal, March 2005

  • Song, Lanxi; Coppola, Domenico; Livingston, Sandy
  • Cancer Biology & Therapy, Vol. 4, Issue 3
  • DOI: 10.4161/cbt.4.3.1496

Immunohistochemical Analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 Expression in Pancreatic Cancers
journal, January 1999

  • Miyamoto, Yoshiharu; Hosotani, Ryo; Wada, Michihiko
  • Oncology, Vol. 56, Issue 1
  • DOI: 10.1159/000011933

Bcl-x L and MCL-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis
journal, January 2009

  • Brotin, Emilie; Meryet-Figuière, Matthieu; Simonin, Karin
  • International Journal of Cancer
  • DOI: 10.1002/ijc.24787

Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-xL is an essential survival protein of human myeloma cells
journal, July 2002

The antiapoptotic member of the Bcl-2 family Mcl-1 is a CTL target in cancer patients
journal, December 2004

Mechanism of Synergy of N-(4-Hydroxyphenyl)Retinamide and ABT-737 in Acute Lymphoblastic Leukemia Cell Lines: Mcl-1 Inactivation
journal, April 2008

  • Kang, Min H.; Wan, Zesheng; Kang, Yun Hee
  • JNCI: Journal of the National Cancer Institute, Vol. 100, Issue 8
  • DOI: 10.1093/jnci/djn076

Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
journal, March 2011

  • Wertz, Ingrid E.; Kusam, Saritha; Lam, Cynthia
  • Nature, Vol. 471, Issue 7336
  • DOI: 10.1038/nature09779

Inducing apoptosis and enhancing chemosensitivity to Gemcitabine via RNA interference targeting Mcl-1 gene in pancreatic carcinoma cell
journal, February 2008

The BCL-2 protein family, BH3-mimetics and cancer therapy
journal, May 2015

  • Delbridge, A. R. D.; Strasser, A.
  • Cell Death & Differentiation, Vol. 22, Issue 7
  • DOI: 10.1038/cdd.2015.50

Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
journal, April 2004

  • Arkin, Michelle R.; Wells, James A.
  • Nature Reviews Drug Discovery, Vol. 3, Issue 4
  • DOI: 10.1038/nrd1343

Structural biology of the Bcl-2 family of proteins
journal, March 2004

  • Petros, Andrew M.; Olejniczak, Edward T.; Fesik, Stephen W.
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1644, Issue 2-3
  • DOI: 10.1016/j.bbamcr.2003.08.012

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer
journal, June 2010

  • Stewart, Michelle L.; Fire, Emiko; Keating, Amy E.
  • Nature Chemical Biology, Vol. 6, Issue 8
  • DOI: 10.1038/nchembio.391

Structural insights into the degradation of Mcl-1 induced by BH3 domains
journal, March 2007

  • Czabotar, P. E.; Lee, E. F.; van Delft, M. F.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 15
  • DOI: 10.1073/pnas.0701297104

Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia
journal, July 2014

  • Kaefer, Aksana; Yang, Jianning; Noertersheuser, Peter
  • Cancer Chemotherapy and Pharmacology, Vol. 74, Issue 3
  • DOI: 10.1007/s00280-014-2530-9

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
journal, January 2013

  • Souers, Andrew J.; Leverson, Joel D.; Boghaert, Erwin R.
  • Nature Medicine, Vol. 19, Issue 2
  • DOI: 10.1038/nm.3048

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
journal, May 2008

Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors
journal, March 2011

  • Gandhi, Leena; Camidge, D. Ross; Ribeiro de Oliveira, Moacyr
  • Journal of Clinical Oncology, Vol. 29, Issue 7
  • DOI: 10.1200/JCO.2010.31.6208

Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer
journal, April 2012

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
journal, October 2016

  • Kotschy, András; Szlavik, Zoltán; Murray, James
  • Nature, Vol. 538, Issue 7626
  • DOI: 10.1038/nature19830

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors
journal, January 2017

Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design
journal, December 2012

  • Friberg, Anders; Vigil, Dominico; Zhao, Bin
  • Journal of Medicinal Chemistry, Vol. 56, Issue 1
  • DOI: 10.1021/jm301448p

Discovery of Tricyclic Indoles That Potently Inhibit Mcl-1 Using Fragment-Based Methods and Structure-Based Design
journal, April 2015

  • Burke, Jason P.; Bian, Zhiguo; Shaw, Subrata
  • Journal of Medicinal Chemistry, Vol. 58, Issue 9
  • DOI: 10.1021/jm501984f

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
journal, February 2016

Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors
journal, December 2016

Biologic and genetic characterization of the novel amyloidogenic lambda light chain–secreting human cell lines, ALMC-1 and ALMC-2
journal, September 2008

[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

The CCP4 suite programs for protein crystallography
journal, September 1994

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization
journal, September 2004

  • Nikolovska-Coleska, Zaneta; Wang, Renxiao; Fang, Xueliang
  • Analytical Biochemistry, Vol. 332, Issue 2
  • DOI: 10.1016/j.ab.2004.05.055

SHELXT – Integrated space-group and crystal-structure determination
journal, January 2015

  • Sheldrick, George M.
  • Acta Crystallographica Section A Foundations and Advances, Vol. 71, Issue 1, p. 3-8
  • DOI: 10.1107/S2053273314026370

Crystal structure determination and refinement via SIR2014
journal, January 2015

  • Burla, Maria Cristina; Caliandro, Rocco; Carrozzini, Benedetta
  • Journal of Applied Crystallography, Vol. 48, Issue 1
  • DOI: 10.1107/S1600576715001132

Structure validation in chemical crystallography
journal, January 2009

  • Spek, Anthony L.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 65, Issue 2, p. 148-155
  • DOI: 10.1107/S090744490804362X
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    • Jiang, Xiangyi; Yu, Ji; Zhou, Zhongxia
    • Medicinal Research Reviews, Vol. 39, Issue 6
    • DOI: 10.1002/med.21581
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