Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

被引：1

作者：

Hartwell, Kimberly A. ^{[1
,2
,3
]}

Miller, Peter G. ^{[2
,3
]}

Mukherjee, Siddhartha ^{[4
,5
]}

Kahn, Alissa R. ^{[6
]}

Stewart, Alison L. ^{[1
]}

Logan, David J. ^{[1
]}

Negri, Joseph M. ^{[1
]}

Duvet, Mildred ^{[1
,4
,5
]}

Jaeras, Marcus ^{[2
,3
]}

Puram, Rishi ^{[2
,3
]}

Dancik, Vlado ^{[1
]}

Al-Shahrour, Fatima ^{[1
,2
,3
]}

Kindler, Thomas ^{[2
,3
]}

Tothova, Zuzana ^{[2
,3
]}

Chattopadhyay, Shrikanta ^{[1
,7
]}

Hasaka, Thomas ^{[1
]}

Narayan, Rajiv ^{[1
]}

Dai, Mingji ^{[1
,8
]}

Huang, Christina ^{[1
]}

Shterental, Sebastian ^{[2
,3
]}

Chu, Lisa P. ^{[2
,3
]}

Haydu, J. Erika ^{[2
,3
]}

Shieh, Jae Hung ^{[6
]}

Steensma, David P. ^{[3
,9
]}

Munoz, Benito ^{[1
]}

Bittker, Joshua A. ^{[1
]}

Shamji, Alykhan F. ^{[1
]}

Clemons, Paul A. ^{[1
]}

Tolliday, Nicola J. ^{[1
]}

Carpenter, Anne E. ^{[1
]}

Gilliland, D. Gary ^{[1
,2
,3
,9
,10
]}

Stern, Andrew M. ^{[1
]}

Moore, Malcolm A. S. ^{[11
]}

Scadden, David T. ^{[1
,4
,5
,7
]}

Schreiber, Stuart L. ^{[1
,8
,10
]}

Ebert, Benjamin L. ^{[1
,2
,3
,9
]}

Golub, Todd R. ^{[1
,3
,10
,12
]}

机构：

[1] Broad Inst, Cambridge, MA 02142 USA

[2] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[6] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA

[7] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[8] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Harvard Univ, Howard Hughes Med Inst, Sch Med, Chevy Chase, MD USA

[11] Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA

[12] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

来源：

NATURE CHEMICAL BIOLOGY | 2013年 / 9卷 / 12期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; PROGENITOR CELLS; STROMAL CELLS; PROTEIN TRANSFERASE; FREQUENCY-ANALYSIS; INDUCED APOPTOSIS; IN-VIVO; CANCER; GENES; MICE;

D O I：

10.1038/NCHEMBIO.1367

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

引用

页码：840 / +

页数：12

共 50 条

[31] Translational potential of a small-molecule silibinin in colorectal cancer: Targeting cancer stem cells and their inflammatory niche.
Agarwal, Rajesh
Agarwal, Chapla
CLINICAL CANCER RESEARCH, 2018, 24 (01) : 81 - 81
[32] Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors
Lin, Tony Eight
Sung, Li-Chin
Chao, Min-Wu
Li, Min
Zheng, Jia-Huei
Sung, Tzu-Ying
Hsieh, Jui-Hua
Yang, Chia-Ron
Lee, Hsueh-Yun
Cho, Er-Chieh
Hsu, Kai-Cheng
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2022, 37 (01) : 226 - 235
[33] Identification of small-molecule inhibitors against SecA by structure-based virtual ligand screening
Evelien De Waelheyns
Kenneth Segers
Marios Frantzeskos Sardis
Jozef Anné
Gerry A F Nicolaes
Anastassios Economou
The Journal of Antibiotics, 2015, 68 : 666 - 673
[34] Allogeneic Stem Cell Transplantation for Patients With Lymphoma and Chronic Lymphocytic Leukemia Following Targeted Small-Molecule Inhibitors
不详
CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY, 2019, 17 (08) : 13 - 14
[35] Identification of small-molecule inhibitors against SecA by structure-based virtual ligand screening
De Waelheyns, Evelien
Segers, Kenneth
Sardis, Marios Frantzeskos
Anne, Jozef
Nicolaes, Gerry A. F.
Economou, Anastassios
JOURNAL OF ANTIBIOTICS, 2015, 68 (11): : 666 - 673
[36] Structure-Based Target-Specific Screening Leads to Small-Molecule CaMKII Inhibitors
Xu, David
Li, Liwei
Zhou, Donghui
Liu, Degang
Hudmon, Andy
Meroueh, Samy O.
CHEMMEDCHEM, 2017, 12 (09) : 660 - 677
[37] Peptidomimetic small-molecule compounds promoting cardiogenesis of stem cells
Se-Woong Oh
Jung Bok Lee
Bora Kim
Sejin Jeon
Min-Kyoung Kim
Ki-Hoan Nam
Jong-Ryul Ha
Mickie Bhatia
Goo Taeg Oh
Dae-Yong Kim
Archives of Pharmacal Research, 2012, 35 : 1979 - 1988
[38] Peptidomimetic small-molecule compounds promoting cardiogenesis of stem cells
Oh, Se-Woong
Lee, Jung Bok
Kim, Bora
Jeon, Sejin
Kim, Min-Kyoung
Nam, Ki-Hoan
Ha, Jong-Ryul
Bhatia, Mickie
Oh, Goo Taeg
Kim, Dae-Yong
ARCHIVES OF PHARMACAL RESEARCH, 2012, 35 (11) : 1979 - 1988
[39] Small-molecule inhibitors of carboxylesterase Notum
Zhao, Yuguang
Jolly, Sarah
Benvegnu, Stefano
Jones, E. Yvonne
Fish, Paul, V
FUTURE MEDICINAL CHEMISTRY, 2021, 13 (11) : 1001 - 1015
[40] Probing Translation with Small-Molecule Inhibitors
Blanchard, Scott C.
Cooperman, Barry S.
Wilson, Daniel N.
CHEMISTRY & BIOLOGY, 2010, 17 (06): : 633 - 645

← 1 2 3 4 5 →