Preparation of 5′-deoxy-5′-amino-5′-C-methyl adenosine derivatives and their activity against DOT1L

Liu, Tongchao; Xie, Wuchen; Liu, Cong; Ren, Huanming; Mao, Yudong; Chen, Guohua; Cheng, Maosheng; Shen, Jingkang; Li, Jia; Zhou, Yubo; Xiong, Bing; Chen, Yue‐Lei

doi:10.1016/j.bmcl.2017.10.019

Cited by 8 publications

(3 citation statements)

References 21 publications

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“…A common strategy is to develop SAM analogs by structurally modifying SAM; most nucleoside inhibitors have been synthesized according to this basis [13][14][15][16][17], and they are generally classified into four categories (Fig. 2).…”

Section: Dot1l Inhibitorsmentioning

confidence: 99%

Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias

Yan

2022

J Hematol Oncol

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Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein–protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.

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Section: Dot1l Inhibitorsmentioning

confidence: 99%

Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias

Yan

2022

J Hematol Oncol

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“…Nevertheless, a phase I trial of pinometostat, a small-molecule DOT1L inhibitor, conducted in children with r/r MLL-associated AML (NCT02141828) demonstrated only a transient reduction in leukemic blast counts [ 54 ]. A phase I/II trial of pinometostat plus standard chemotherapy (NCT03724084)in pediatric and adult patients with newly diagnosed MLL-rearranged AML is currently ongoing [ 55 ]. Moreover, results with combined pinometostat and FLT3 inhibitor were recently reported for pediatric AML patients, confirming that targeting DOT1L with pinometostat sensitizes AML cells to further treatment with the multi-kinase inhibitor sorafenib [ 56 ].…”

Section: Novel Potential Therapiesmentioning

confidence: 99%

High-Risk Acute Myeloid Leukemia: A Pediatric Prospective

et al. 2022

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Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment.

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“…All these factors can be considered potential actionable targets for AMLs bearing MLL aberrations. It is important to notice that, for several of them, synthetic inhibitors are available and have been validated, and some of them are being tested in preclinical models or clinical trials [ 75 , 76 , 77 , 78 , 79 , 80 ].…”

Section: Mixed Lineage Leukemia (Mll) As a Versatile Tool To Dissementioning

confidence: 99%

Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

et al. 2018

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Acute myeloid leukemia (AML), the most common acute leukemia in the adult, is believed to arise as a consequence of multiple molecular events that confer on primitive hematopoietic progenitors unlimited self-renewal potential and cause defective differentiation. A number of genetic aberrations, among which a variety of gene fusions, have been implicated in the development of a transformed phenotype through the generation of dysfunctional molecules that disrupt key regulatory mechanisms controlling survival, proliferation, and differentiation in normal stem and progenitor cells. Such genetic aberrations can be recreated experimentally to a large extent, to render normal hematopoietic stem cells “bad”, analogous to the leukemic stem cells. Here, we wish to provide a brief outline of the complementary experimental approaches, largely based on gene delivery and more recently on gene editing, employed over the last two decades to gain insights into the molecular mechanisms underlying AML development and progression and on the prospects that their applications offer for the discovery and validation of innovative therapies.

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Preparation of 5′-deoxy-5′-amino-5′-C-methyl adenosine derivatives and their activity against DOT1L

Cited by 8 publications

References 21 publications

Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias

Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias

High-Risk Acute Myeloid Leukemia: A Pediatric Prospective

Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches

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