Molecular Pathways: Protein Methyltransferases in Cancer

被引:50
作者
Copeland, Robert A. [1 ]
机构
[1] Epizyme Inc, Cambridge, MA 02139 USA
关键词
MIXED-LINEAGE LEUKEMIA; B-CELL LYMPHOMAS; HISTONE METHYLTRANSFERASE; MULTIPLE-MYELOMA; TRANSCRIPTIONAL ELONGATION; DRUG DISCOVERY; LYSINE; 27; MLL; METHYLATION; DOT1L;
D O I
10.1158/1078-0432.CCR-13-0223
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The protein methyltransferases (PMT) constitute a large and important class of enzymes that catalyze site-specific methylation of lysine or arginine residues on histones and other proteins. Site-specific histone methylation is a critical component of chromatin regulation of gene transcription-a pathway that is often genetically altered in human cancers. Oncogenic alterations (e.g., mutations, chromosomal translocations, and others) of PMTs, or of associated proteins, have been found to confer unique dependencies of cancer cells on the activity of specific PMTs. Examples of potent, selective small-molecule inhibitors of specific PMTs are reviewed that have been shown to kill cancers cells bearing such oncogenic alterations, while having minimal effect on proliferation of nonaltered cells. Selective inhibitors of the PMTs, DOT1L and EZH2, have entered phase I clinical studies and additional examples of selective PMT inhibitors are likely to enter the clinic soon. The current state of efforts toward clinical testing of selective PMT inhibitors as personalized cancer therapeutics is reviewed here. (C)2013 AACR.
引用
收藏
页码:6344 / 6350
页数:7
相关论文
共 45 条
[1]   Epigenetic protein families: a new frontier for drug discovery [J].
Arrowsmith, Cheryl H. ;
Bountra, Chas ;
Fish, Paul V. ;
Lee, Kevin ;
Schapira, Matthieu .
NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (05) :384-400
[2]   Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L [J].
Basavapathruni, Aravind ;
Jin, Lei ;
Daigle, Scott R. ;
Majer, Christina R. A. ;
Therkelsen, Carly A. ;
Wigle, Tim J. ;
Kuntz, Kevin W. ;
Chesworth, Richard ;
Pollock, Roy M. ;
Scott, Margaret P. ;
Moyer, Mikel P. ;
Richon, Victoria M. ;
Copeland, Robert A. ;
Olhava, Edward J. .
CHEMICAL BIOLOGY & DRUG DESIGN, 2012, 80 (06) :971-980
[3]   MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L [J].
Bernt, Kathrin M. ;
Zhu, Nan ;
Sinha, Amit U. ;
Vempati, Sridhar ;
Faber, Joerg ;
Krivtsov, Andrei V. ;
Feng, Zhaohui ;
Punt, Natalie ;
Daigle, Amanda ;
Bullinger, Lars ;
Pollock, Roy M. ;
Richon, Victoria M. ;
Kung, Andrew L. ;
Armstrong, Scott A. .
CANCER CELL, 2011, 20 (01) :66-78
[4]   The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling [J].
Bitoun, Emmanuelle ;
Oliver, Peter L. ;
Davies, Kay E. .
HUMAN MOLECULAR GENETICS, 2007, 16 (01) :92-106
[5]  
Bodor C, 2012, P 54 ASH ANN M EXP 2
[6]  
Caparros, 2007, EPIGENETICS
[7]   Structural and sequence motifs of protein (histone) methylation enzymes [J].
Cheng, XD ;
Collins, RE ;
Zhang, X .
ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE, 2005, 34 :267-294
[8]   The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts [J].
Chesi, M ;
Nardini, E ;
Lim, RSC ;
Smith, KD ;
Kuehl, WM ;
Bergsagel, PL .
BLOOD, 1998, 92 (09) :3025-3034
[9]   Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics [J].
Copeland, R. A. ;
Moyer, M. P. ;
Richon, V. M. .
ONCOGENE, 2013, 32 (08) :939-946
[10]  
Copeland RA, 2013, EVALUATION OF ENZYME INHIBITORS IN DRUG DISCOVERY: A GUIDE FOR MEDICINAL CHEMISTS AND PHARMACOLOGISTS, 2ND EDITION, P1, DOI 10.1002/9781118540398