Literature DB >> 23879463

A medicinal chemistry perspective for targeting histone H3 lysine-79 methyltransferase DOT1L.

Justin L Anglin1, Yongcheng Song.   

Abstract

Histone H3 lysine79 (H3K79) methyltransferase DOT1L plays an important role in the activation and maintenance of gene transcription. It is essential for embryonic development as well as normal functions of the hematopoietic system, heart, and kidney in adults. DOT1L has been found to be a drug target for acute leukemia with mixed lineage leukemia (MLL) gene translocations. The rearranged onco-MLL can recruit DOT1L, causing aberrant H3K79 methylation, overexpression of leukemia relevant genes, and eventually leukemogenesis. Potent DOT1L inhibitors possess selective activity against this type of leukemia in cell-based and animal studies, with the most advanced compound being in clinical trials. In the medicinal chemistry point of view, we review the biochemistry, cancer biology, and current inhibitors of DOT1L, as well as biophysical (including X-ray crystallographic) investigation of DOT1L-inhibitor interactions. Potential future directions in the context of drug discovery and development targeting DOT1L are discussed.

Entities:  

Mesh：

Substances：

Year:  2013        PMID： 23879463      PMCID： PMC4109313          DOI： 10.1021/jm4007752

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  61 in total

1.  DOT1L regulates dystrophin expression and is critical for cardiac function.

Authors:  Anh T Nguyen; Bin Xiao; Ronald L Neppl; Eric M Kallin; Juan Li; Taiping Chen; Da-Zhi Wang; Xiao Xiao; Yi Zhang
Journal:  Genes Dev       Date:  2011-02-01       Impact factor: 11.361

2.  Combinatorial patterns of histone acetylations and methylations in the human genome.

Authors:  Zhibin Wang; Chongzhi Zang; Jeffrey A Rosenfeld; Dustin E Schones; Artem Barski; Suresh Cuddapah; Kairong Cui; Tae-Young Roh; Weiqun Peng; Michael Q Zhang; Keji Zhao
Journal:  Nat Genet       Date:  2008-06-15       Impact factor: 38.330

3.  Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

Authors:  Scott R Daigle; Edward J Olhava; Carly A Therkelsen; Aravind Basavapathruni; Lei Jin; P Ann Boriack-Sjodin; Christina J Allain; Christine R Klaus; Alejandra Raimondi; Margaret Porter Scott; Nigel J Waters; Richard Chesworth; Mikel P Moyer; Robert A Copeland; Victoria M Richon; Roy M Pollock
Journal:  Blood       Date:  2013-06-25       Impact factor: 22.113

4.  Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study.

Authors:  K Mrózek; K Heinonen; D Lawrence; A J Carroll; P R Koduru; K W Rao; M P Strout; R E Hutchison; J O Moore; R J Mayer; C A Schiffer; C D Bloomfield
Journal:  Blood       Date:  1997-12-01       Impact factor: 22.113

5.  Dot1a contains three nuclear localization signals and regulates the epithelial Na+ channel (ENaC) at multiple levels.

Authors:  Mary Rose Reisenauer; Steven W Wang; Yang Xia; Wenzheng Zhang
Journal:  Am J Physiol Renal Physiol       Date:  2010-04-28

6.  Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain.

Authors:  Qin Feng; Hengbin Wang; Huck Hui Ng; Hediye Erdjument-Bromage; Paul Tempst; Kevin Struhl; Yi Zhang
Journal:  Curr Biol       Date:  2002-06-25       Impact factor: 10.834

7.  ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children.

Authors:  C A Felix; M R Hosler; N J Winick; M Masterson; A E Wilson; B J Lange
Journal:  Blood       Date:  1995-06-01       Impact factor: 22.113

8.  Gene expression profiling of pediatric acute myelogenous leukemia.

Authors:  Mary E Ross; Rami Mahfouz; Mihaela Onciu; Hsi-Che Liu; Xiaodong Zhou; Guangchun Song; Sheila A Shurtleff; Stanley Pounds; Cheng Cheng; Jing Ma; Raul C Ribeiro; Jeffrey E Rubnitz; Kevin Girtman; W Kent Williams; Susana C Raimondi; Der-Cherng Liang; Lee-Yung Shih; Ching-Hon Pui; James R Downing
Journal:  Blood       Date:  2004-06-29       Impact factor: 22.113

9.  Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.

Authors:  D C Tkachuk; S Kohler; M L Cleary
Journal:  Cell       Date:  1992-11-13       Impact factor: 41.582

10.  Chromatin-modifying enzymes as modulators of reprogramming.

Authors:  Tamer T Onder; Nergis Kara; Anne Cherry; Amit U Sinha; Nan Zhu; Kathrin M Bernt; Patrick Cahan; B Ogan Marcarci; Juli Unternaehrer; Piyush B Gupta; Eric S Lander; Scott A Armstrong; George Q Daley
Journal:  Nature       Date:  2012-03-04       Impact factor: 49.962
View more
  24 in total

1.  Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.

Authors:  Ting-Rong Chern; Liu Liu; Elyse Petrunak; Jeanne A Stuckey; Mi Wang; Denzil Bernard; Haibin Zhou; Shirley Lee; Yali Dou; Shaomeng Wang
Journal:  ACS Med Chem Lett       Date:  2020-05-14       Impact factor: 4.345

Review 2.  Inhibitors of Protein Methyltransferases and Demethylases.

Authors:  H Ümit Kaniskan; Michael L Martini; Jian Jin
Journal:  Chem Rev       Date:  2017-03-24       Impact factor: 60.622

3.  Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.

Authors:  Henrik Möbitz; Rainer Machauer; Philipp Holzer; Andrea Vaupel; Frédéric Stauffer; Christian Ragot; Giorgio Caravatti; Clemens Scheufler; Cesar Fernandez; Ulrich Hommel; Ralph Tiedt; Kim S Beyer; Chao Chen; Hugh Zhu; Christoph Gaul
Journal:  ACS Med Chem Lett       Date:  2017-02-14       Impact factor: 4.345

4.  Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach.

Authors:  Chao Chen; Hugh Zhu; Frédéric Stauffer; Giorgio Caravatti; Susanne Vollmer; Rainer Machauer; Philipp Holzer; Henrik Möbitz; Clemens Scheufler; Martin Klumpp; Ralph Tiedt; Kim S Beyer; Keith Calkins; Daniel Guthy; Michael Kiffe; Jeff Zhang; Christoph Gaul
Journal:  ACS Med Chem Lett       Date:  2016-06-01       Impact factor: 4.345

Review 5.  Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond.

Authors:  Chun-Wei Chen; Scott A Armstrong
Journal:  Exp Hematol       Date:  2015-06-25       Impact factor: 3.084

6.  Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.

Authors:  Clemens Scheufler; Henrik Möbitz; Christoph Gaul; Christian Ragot; Céline Be; César Fernández; Kim S Beyer; Ralph Tiedt; Frédéric Stauffer
Journal:  ACS Med Chem Lett       Date:  2016-06-06       Impact factor: 4.345

7.  Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.

Authors:  Manuela Sabatino; Dante Rotili; Alexandros Patsilinakos; Mariantonietta Forgione; Daniela Tomaselli; Fréderic Alby; Paola B Arimondo; Antonello Mai; Rino Ragno
Journal:  J Comput Aided Mol Des       Date:  2018-01-15       Impact factor: 3.686

8.  Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library.

Authors:  Garrett S Gibbons; Amarraj Chakraborty; Sierrah M Grigsby; Afoma C Umeano; Chenzhong Liao; Omar Moukha-Chafiq; Vibha Pathak; Bini Mathew; Young-Tae Lee; Yali Dou; Stephan C Schürer; Robert C Reynolds; Timothy S Snowden; Zaneta Nikolovska-Coleska
Journal:  Eur J Med Chem       Date:  2020-01-02       Impact factor: 6.514

9.  The histone methyltransferase DOT1L: regulatory functions and a cancer therapy target.

Authors:  Matthew Wong; Patsie Polly; Tao Liu
Journal:  Am J Cancer Res       Date:  2015-08-15       Impact factor: 6.166

Review 10.  SAM/SAH Analogs as Versatile Tools for SAM-Dependent Methyltransferases.

Authors:  Jing Zhang; Yujun George Zheng
Journal:  ACS Chem Biol       Date:  2015-11-16       Impact factor: 5.100
View more

北京卡尤迪生物科技股份有限公司 © 2022-2023.