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Title: Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo

Abstract

Chromosomal translocations affecting mixed lineage leukemia gene ( MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. In this paper, we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. In conclusion, overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [3];  [1];  [4];  [3];  [1];  [1];  [1];  [5];  [1] more »;  [1];  [1];  [1] « less
  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. Univ. of Michigan, Ann Arbor, MI (United States); Medlmmune, LLC, Gaithersburg, MD (United States)
  3. Weill Medical College of Cornell Univ., New York, NY (United States)
  4. Univ. of Pennsylvania, Philadelphia, PA (United States)
  5. Univ. of Michigan, Ann Arbor, MI (United States); Indiana Univ., Indianapolis, IN (United States)
Publication Date:
Research Org.:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1247185
Alternate Identifier(s):
OSTI ID: 1344392
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Published Article
Journal Name:
Cancer Cell
Additional Journal Information:
Journal Volume: 27; Journal Issue: 4; Journal ID: ISSN 1535-6108
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Borkin, Dmitry, He, Shihan, Miao, Hongzhi, Kempinska, Katarzyna, Pollock, Jonathan, Chase, Jennifer, Purohit, Trupta, Malik, Bhavna, Zhao, Ting, Wang, Jingya, Wen, Bo, Zong, Hongliang, Jones, Morgan, Danet-Desnoyers, Gwenn, Guzman, Monica L., Talpaz, Moshe, Bixby, Dale L., Sun, Duxin, Hess, Jay L., Muntean, Andrew G., Maillard, Ivan, Cierpicki, Tomasz, and Grembecka, Jolanta. Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. United States: N. p., 2015. Web. doi:10.1016/j.ccell.2015.02.016.
Borkin, Dmitry, He, Shihan, Miao, Hongzhi, Kempinska, Katarzyna, Pollock, Jonathan, Chase, Jennifer, Purohit, Trupta, Malik, Bhavna, Zhao, Ting, Wang, Jingya, Wen, Bo, Zong, Hongliang, Jones, Morgan, Danet-Desnoyers, Gwenn, Guzman, Monica L., Talpaz, Moshe, Bixby, Dale L., Sun, Duxin, Hess, Jay L., Muntean, Andrew G., Maillard, Ivan, Cierpicki, Tomasz, & Grembecka, Jolanta. Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo. United States. doi:10.1016/j.ccell.2015.02.016.
Borkin, Dmitry, He, Shihan, Miao, Hongzhi, Kempinska, Katarzyna, Pollock, Jonathan, Chase, Jennifer, Purohit, Trupta, Malik, Bhavna, Zhao, Ting, Wang, Jingya, Wen, Bo, Zong, Hongliang, Jones, Morgan, Danet-Desnoyers, Gwenn, Guzman, Monica L., Talpaz, Moshe, Bixby, Dale L., Sun, Duxin, Hess, Jay L., Muntean, Andrew G., Maillard, Ivan, Cierpicki, Tomasz, and Grembecka, Jolanta. Thu . "Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo". United States. doi:10.1016/j.ccell.2015.02.016.
@article{osti_1247185,
title = {Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo},
author = {Borkin, Dmitry and He, Shihan and Miao, Hongzhi and Kempinska, Katarzyna and Pollock, Jonathan and Chase, Jennifer and Purohit, Trupta and Malik, Bhavna and Zhao, Ting and Wang, Jingya and Wen, Bo and Zong, Hongliang and Jones, Morgan and Danet-Desnoyers, Gwenn and Guzman, Monica L. and Talpaz, Moshe and Bixby, Dale L. and Sun, Duxin and Hess, Jay L. and Muntean, Andrew G. and Maillard, Ivan and Cierpicki, Tomasz and Grembecka, Jolanta},
abstractNote = {Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. In this paper, we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. In conclusion, overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.},
doi = {10.1016/j.ccell.2015.02.016},
journal = {Cancer Cell},
number = 4,
volume = 27,
place = {United States},
year = {Thu Mar 26 00:00:00 EDT 2015},
month = {Thu Mar 26 00:00:00 EDT 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.ccell.2015.02.016

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Cited by: 57 works
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