Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia

Song, Moo-Kon; Park, Byeong-Bae; Uhm, Jieun

doi:10.3390/ijms232012708

Cited by 12 publications

(10 citation statements)

References 93 publications

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“…132 Despite the clinical availability of FLT3 inhibitors, their impact on survival outcomes remains modest. 133 In 2023, Yashar et al reported that combining an LSD1 inhibitor GSK-2879552 and an FLT3 inhibitor Quizartinib exhibited a synergistic effect in inducing cell death in FLT3 mutant AML (Table 2). 101 This drug combination simultaneously disrupted the binding of STAT5, LSD1, and GFI1 from the MYC blood superenhancer complex, leading to the repression of MYC expression and causing the accumulation of repressive H3K9me1 at MYC target genes.…”

Section: Combination Of Lsd1 Inhibitor and Flt3mentioning

confidence: 99%

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Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Shen,

Wang,

Wang

et al. 2024

J. Med. Chem.

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Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

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Section: Combination Of Lsd1 Inhibitor and Flt3mentioning

confidence: 99%

“…In recent years, targeting FLT3 has been an integral component of treatment regimens for FLT3-ITD/TKD-mutated AML patients, leading to significantly extended survival rates . Despite the clinical availability of FLT3 inhibitors, their impact on survival outcomes remains modest …”

Section: Combination Of Lsd1 Inhibitors and Other Target-based Inhibi...mentioning

confidence: 99%

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Shen,

Wang,

Wang

et al. 2024

J. Med. Chem.

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“…Upon maturation into lymphoid or myeloid cells, the expression of FLT3 is either reduced or lost altogether. The receptor comprises five immunoglobulin-like domains in the extracellular region, a juxtamembrane (JM) domain, a tyrosine kinase domain (TKD) divided by a kinase insert domain, and a C-terminal domain in the intracellular region [2,5,6]. The structure of FLT3 is shown in Figure 1.…”

Section: Flt3 Structurementioning

confidence: 99%

A Review of FLT3 Kinase Inhibitors in AML

Negotei,

Colita,

Mitu

et al. 2023

JCM

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Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6–8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient’s condition and susceptibility.

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“…These inhibitors aim to counteract the aberrant signaling pathways triggered by FLT3 mutations, thereby hindering the growth and survival of leukemia cells [32]. The integration of FLT3 mutational status into the risk strati cation of AML patients has become essential for treatment decision-making [33]. The identi cation of FLT3 mutations not only informs prognosis but also guides the selection of targeted therapies, fostering a more personalized and effective approach to managing AML [34].…”

Section: Introductionmentioning

confidence: 99%

Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

Dasgupta,

Chatterjee,

Mondal

et al. 2023

Preprint

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The call for implementing inhibitory methods in cancer treatment has intensified. Recently, cancer has deeply affected society, with Acute Myeloid Leukemia (AML) being identified as one of the most formidable and lethal adversaries. This research investigates the intricate interactions between vitamins A, B, C, D, E, and K and critical signaling pathways, such as NPM1, FLT3, and RUNX1, uncovering meaningful associations. Employing the precision of molecular docking with Autodock Vina 1.5.7, a thorough exploration of these interactions was carried out. The analysis entailed a detailed examination of hydrophilic and hydrophobic aspects using LigPlot, complemented by additional insights visualized through PyMol. The considerable occurrence of observed hydrophilic interactions, coupled with the noteworthy binding energy, underscores the potential of vitamin-related derivatives as promising contenders for inhibitory cancer treatments. However, the realization of this potential is contingent upon subsequent investigations, including a comprehensive exploration through RT-qPCR studies. While the study has successfully identified significant interactions, the intricate dynamics of gene expression necessitate thorough studies to attain a holistic understanding of both upregulation and downregulation. In conclusion, the revelations from this study not only set the stage for potential inhibitory treatments of AML through the strategic application of vitamin-based derivatives but also underscore the transformative capabilities of these derivatives. In future research endeavors, should vitamin interactions reveal substantial downregulation, these derivatives stand poised to spearhead innovative cancer treatments, marking a transformative era in targeted drug delivery.

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Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia

Cited by 12 publications

References 93 publications

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy

A Review of FLT3 Kinase Inhibitors in AML

Targeting AML Growth: Vitamins' Influence on FLT3, NPM1, and RUNX1 Interactions

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