Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

Luo, Minghao; Wang, Hui; Zou, Yi; Zhang, Shengping; Jian-hu, Xiao; Jiang, Guangde; Zhang, Yihua; Lai, Yisheng

doi:10.1016/j.jmgm.2016.06.011

Cited by 12 publications

(10 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Continuous intravenous infusion of the compound caused tumor regression and prolonged survival in mice and rat xenograft models of MLL-r leukemias ( 203 ). Unfortunately, the lack of oral bioavailability and short half-life of the drug currently mandate the continuous IV infusion, resulting in efforts to develop alternative Dot1L inhibitors, which maintain specificity and efficacy but are easier to administer ( 205 ). Data from the phase I/II clinical trials are forthcoming, but it will be crucial to correlate mechanistic effect (i.e., reduction of H3K79 methylation) with outcomes in these patients.…”

Section: Mll Specific Pathways and Targeted Inhibitors In Early Clinimentioning

confidence: 99%

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

2017

View full text Add to dashboard Cite

The mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than 1 year of age at diagnosis (primarily acute lymphoblastic leukemias) and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents—so-called therapy-related leukemias. In general, outcomes for all of these patients remain poor when compared to patients with non-MLL1 rearranged leukemias. In this review, we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research, which may lead to more effective targeted therapies for affected patients.

show abstract

Section: Mll Specific Pathways and Targeted Inhibitors In Early Clinimentioning

confidence: 99%

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

2017

View full text Add to dashboard Cite

show abstract

“…This is, for instance, also the case for: the pyrimidyl-aminoquinoline derivative 9e , that interacts with DOT1L at the µM range and reduces HOXA9 and MEIS1 expression [139];compounds 3 and 9, identified by high throughput screening [140]; DC_L115, which binds DOT1L at sub-micromolar concentration [141];2-chloro benzothiophene derivative 12 and aza-benzimidazole derivative 13 , as two orally bioavailable DOT1L inhibitors [142]; the phenoxyacetamide derivatives L01, L03, L04, and L05, identified by hierarchical docking-based virtual screening and molecular dynamic simulation [143]; and massonianoside B, identified by use of a pharmacophore-based in silico screening [144]. …”

Section: Indirect Targeting Of Hoxa9 At the Expression Levelmentioning

confidence: 99%

“…the phenoxyacetamide derivatives L01, L03, L04, and L05, identified by hierarchical docking-based virtual screening and molecular dynamic simulation [143];…”

Section: Indirect Targeting Of Hoxa9 At the Expression Levelmentioning

confidence: 99%

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

Lambert

Alioui

Jambon

et al. 2019

Cancers

View full text Add to dashboard Cite

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an “undruggable” target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.

show abstract

“…Novel structures have been disclosed such as ( 32 ), ( 33 ) and ( 34 ) that also show a SAM-competitive mechanism to inhibit DOT1L [111,112]. Other derivatives with IC 50 in the micromolar ranges have been identified by means of docking screenings and in silico studies as well [113,114]. …”

Section: Inhibition Of Histone Methylationmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

View full text Add to dashboard Cite

Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

show abstract

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

Cited by 12 publications

References 62 publications

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

Contact Info

Product

Resources

About