Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo

被引：297

作者：

Borkin, Dmitry ^{[1
]}

He, Shihan ^{[1
]}

Miao, Hongzhi ^{[1
]}

Kempinska, Katarzyna ^{[1
]}

Pollock, Jonathan ^{[1
,2
]}

Chase, Jennifer ^{[3
,4
]}

Purohit, Trupta ^{[1
]}

Malik, Bhavna ^{[1
]}

Zhao, Ting ^{[5
]}

Wang, Jingya ^{[1
]}

Wen, Bo ^{[5
]}

Zong, Hongliang ^{[9
]}

Jones, Morgan ^{[3
,4
,6
]}

Danet-Desnoyers, Gwenn ^{[10
]}

Guzman, Monica L. ^{[9
]}

Talpaz, Moshe ^{[7
]}

Bixby, Dale L. ^{[7
]}

Sun, Duxin ^{[5
]}

Hess, Jay L. ^{[1
,11
]}

Muntean, Andrew G. ^{[1
]}

Maillard, Ivan ^{[3
,7
,8
]}

Cierpicki, Tomasz ^{[1
]}

Grembecka, Jolanta ^{[1
]}

机构：

[1] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Grad Program Mol & Cellular Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Inst Life Sci, Ctr Stem Cell Biol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Grad Program Cellular & Mol Biol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Med Scientist Training Program, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA

[9] Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10065 USA

[10] Univ Penn, Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[11] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA

来源：

CANCER CELL | 2015年 / 27卷 / 04期

基金：

美国国家卫生研究院;

关键词：

MIXED-LINEAGE LEUKEMIA; HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; FUSION PROTEINS; METHYLATION; CHROMATIN; THERAPY; MLL-AF9; TARGET; GENES;

D O I：

10.1016/j.ccell.2015.02.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. Here 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 mousemodels of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. 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.

引用

页码：589 / 602

页数：14

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