Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases

Cioccio, Joseph; Claxton, David F.

doi:10.1080/13543784.2019.1584610

Cited by 13 publications

(7 citation statements)

References 114 publications

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“…The inhibitors were tested on FLT3-ITD positive MV4-11 cells (2 FLT3-ITD alleles). We chose such cells because FLT3-ITD positive AML is a clinically unresolved issue [ 46 , 47 , 48 , 49 , 50 , 51 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

Ibrahim

Abdelsalam

Zeyn

et al. 2021

IJMS

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Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

Ibrahim

Abdelsalam

Zeyn

et al. 2021

IJMS

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“…We studied the effect of TKIs on lysosomal capacity in human leukemia K562 and HL-60 cell lines representing models for chronic myeloid (CML) leukemia and acute myeloid leukemia (AML), respectively. At the present time, patients with CML are successfully treated with TKIs (e.g., IM, nilotinib, and dasatinib) and clinical trials are underway to test TKIs for the treatment of AML [35,36]. Given that the cytotoxic effect of weak base drugs can be compromised by lysosomal sequestration [10][11][12], investigating the effect of TKIs on the sequestration capacity of lysosomal compartment in K562 and HL-60 cells is of great importance.…”

Section: Resultsmentioning

confidence: 99%

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

2020

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Lysosomal sequestration of anticancer therapeutics lowers their cytotoxic potential, reduces drug availability at target sites, and contributes to cancer resistance. Only recently has it been shown that lysosomal sequestration of weak base drugs induces lysosomal biogenesis mediated by activation of transcription factor EB (TFEB) which, in turn, enhances their accumulation capacity, thereby increasing resistance to these drugs. Here, we addressed the question of whether lysosomal biogenesis is the only mechanism that increases lysosomal sequestration capacity. We found that lysosomal sequestration of some tyrosine kinase inhibitors (TKIs), gefitinib (GF) and imatinib (IM), induced expansion of the lysosomal compartment. However, an expression analysis of lysosomal genes, including lysosome-associated membrane proteins 1, 2 (LAMP1, LAMP2), vacuolar ATPase subunit B2 (ATP6V1B2), acid phosphatase (ACP), and galactosidase beta (GLB) controlled by TFEB, did not reveal increased expression. Instead, we found that both studied TKIs, GF and IM, induced lysosomal fusion which was dependent on nicotinic acid adenine dinucleotide phosphate (NAADP) mediated Ca2+signaling. A theoretical analysis revealed that lysosomal fusion is sufficient to explain the enlargement of lysosomal sequestration capacity. In conclusion, we demonstrated that extracellular TKIs, GF and IM, induced NAADP/Ca2+ mediated lysosomal fusion, leading to enlargement of the lysosomal compartment with significantly increased sequestration capacity for these drugs without apparent lysosomal biogenesis.

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“…[126][127][128][129][130] There has been an extreme effort in the development of TKIs against a variety of cancers, including hematologic malignancies such as AML. 131,132 These are classified as type I, II, and III inhibitors, with type I inhibitors binding to ATP pocket of an active protein kinase domain; type II inhibitors bind to an inactive protein kinase domain; type III inhibitors bind to allosteric sites that are not part of the active site. 44,133 Though there are limitations in specificity, targeting RTK pathways is of extreme importance in AML and both preclinical and clinical studies have demonstrated promising results thus far.…”

Section: Aml Clinical Outcomesmentioning

confidence: 99%

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

Carter

Hege

Yang

et al. 2020

Sig Transduct Target Ther

141

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Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival. Here we review the development of novel therapeutics in targeting apoptosis, receptor tyrosine kinase (RTK) signaling, hedgehog (HH) pathway, mitochondrial function, DNA repair, and c-Myc signaling. There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells. In addition, we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways. We also describe the complexity of targeting leukemia stem cells (LSCs) as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival. This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

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Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases

Cited by 13 publications

References 114 publications

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

Synthesis, Molecular Docking and Biological Characterization of Pyrazine Linked 2-Aminobenzamides as New Class I Selective Histone Deacetylase (HDAC) Inhibitors with Anti-Leukemic Activity

Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

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