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

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:
Grant/Contract Number:
AC02-06CH11357
Type:
Published Article
Journal Name:
Cancer Cell
Additional Journal Information:
Journal Volume: 27; Journal Issue: 4; Journal ID: ISSN 1535-6108
Publisher:
Elsevier
Research Org:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1247185
Alternate Identifier(s):
OSTI ID: 1344392