Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization DOI Creative Commons

Hsin-Huei Chang,

Lung-Chun Lee,

Tsu Hsu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated various cancers but minimally expressed normal proliferating cells. In contrast, MTHFD1, which performs similar functions, predominantly Therefore, targeting MTHFD2 with selective inhibitors holds promise for broader therapeutic window reduced toxicity and fewer side effects. This study identified 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications SAR studies. Structural biology investigations revealed substitutions the phenyl ring tail region modulate potency selectivity toward MTHFD2. Additionally, comprehensive cell screening platform acute myeloid leukemia cells FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds Alimta. Compound 16e emerged as leading candidate, demonstrating superior inhibition MTHFD2, favorable pharmacokinetics, potent antitumor efficacy MOLM-14 xenograft models.

Language: Английский

IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response DOI Creative Commons

Mingyue Yao,

Wenzhong Yan, Wang Yf

et al.

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Feb. 15, 2025

Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating potential epigenetic therapies. However, poor specificity of pan-histone deacetylase (HDACis) leads undesirable adverse effects, prompting isoform-specific HDACis. This study aims explore antileukemic activities mechanisms IHCH9033, a novel class I HDACi, alone or combined FLT3i in AML. The viability AML cell lines primary cells treated HDACis combination was detected by MTT CCK8 assay. Flow cytometry utilized examine apoptosis, cycle progression ROS production. RNA sequencing analysis, RT-qPCR, western blotting, co-immunoprecipitation assays were employed elucidate molecule mechanisms. vivo anti-leukemia efficacy tested xenografted mice models derived from patients. Here, we identified selective which exhibited an increased antitumor effect through effectively eliminating burden overcoming resistance FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair cells, leading accumulation damage that eventually resulted arrest apoptosis. Additionally, induced HSP90 ubiquitination, proteasomal degradation FLT3, thereby inhibiting downstream signaling. Notably, maintained its potency both FLT3i-resistant primary-resistant patient samples, exerted strong synergy quizartinib, tumor regression FLT3-ITD/TKD xenografts. In patient-derived xenografts, combination, led nearly complete eradication burden, without significant effects. Our shows HDACi desirable pharmacological profile, is promising drug candidate AML, suggests strategy combining FLT3is clinical trials increase overcome resistance, thus potentially providing curative option.

Language: Английский

Citations

1
Current knowledge about FLT3 gene mutations, exploring the isoforms, and protein importance in AML DOI

Diana Macečková,

Lenka Vaňková, Monika Holubová

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: April 16, 2024

Language: Английский

Citations

6
The Molecular Context of Oxidant Stress Response in Cancer Establishes ALDH1A1 as a Critical Target: What This Means for Acute Myeloid Leukemia DOI Open Access
Garrett M. Dancik, Lokman Varışlı, Spiros Vlahopoulos

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9372 - 9372

Published: May 27, 2023

The protein family of aldehyde dehydrogenases (ALDH) encompasses nineteen members. ALDH1 subfamily consists enzymes with similar activity, having the capacity to neutralize lipid peroxidation products and generate retinoic acid; however, only ALDH1A1 emerges as a significant risk factor in acute myeloid leukemia. Not is gene on average significantly overexpressed poor prognosis group at RNA level, but its product, protects leukemia cells from byproducts. This protect can be ascribed stability enzyme under conditions oxidant stress. evident both vitro, well mouse xenografts those cells, shielding effectively number potent antineoplastic agents. However, role has been unclear past due evidence that normal often have higher dehydrogenase activity than leukemic cells. being true, expression associated prognosis. It hence imperative methodically targeted, particularly for patients overexpress RNA.

Language: Английский

Citations

15
Reactive oxygen species and aldehyde dehydrogenase 1A as prognosis and theragnostic biomarker in acute myeloid leukaemia patients DOI Creative Commons
Geoffroy Venton, Julien Colle, Antoine Tichadou

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(19)

Published: Oct. 1, 2024

Acute myeloid leukaemia (AML) remains a major unmet medical, despite recent progress in targeted molecular therapies. One aspect of leukaemic cell resistance to chemotherapy is the development clones with increased capacity respond cellular stress and production reactive oxygen species (ROS), thanks particular high aldehyde dehydrogenases (ALDH) 1A1/2 activity. At diagnosis, ROS level ALDH1A1/2 activity AML patients BM are correlated different ELN 2022 prognostic groups overall survival (OS). A significant lower was observed favourable ELN2022 subgroup compared intermediate adverse group (p < 0.01). In same way, levels were significantly 0.0001) 0.0002).

Language: Английский

Citations

4
Role of SIRT5 in cancer. Friend or Foe? DOI
Francisco Alejandro Lagunas‐Rangel

Biochimie, Journal Year: 2023, Volume and Issue: 209, P. 131 - 141

Published: Feb. 20, 2023

Language: Английский

Citations

9
DNA damage accumulation and repair defects in FLT3‐ITD acute myeloid leukemia: Implications for clonal evolution and disease progression DOI Creative Commons
Francisco Alejandro Lagunas‐Rangel

Hematological Oncology, Journal Year: 2022, Volume and Issue: 41(1), P. 26 - 38

Published: Sept. 22, 2022

Abstract Acute myeloid leukemia is a group of hematological diseases that have high mortality rate. During the development this pathology, hematopoietic cells acquire chromosomal rearrangements and multiple genetic mutations, including FLT3‐ITD. FLT3‐ITD marker associated with poor clinical prognosis involves activation pathways such as PI3K/AKT, MAPK/ERK, JAK/STAT favor survival proliferation leukemic cells. In addition, leads to overproduction reactive oxygen species defective DNA damage repair, both implicated in appearance new mutations clones. Thus, purpose review illustrate molecular mechanisms through which generates instability how it facilitates clonal evolution generation more resistant aggressive Likewise, article discusses feasibility combined therapies FLT3 inhibitors repair pathways.

Language: Английский

Citations

15
Chromothripsis in hematologic malignancies DOI
Francisco Alejandro Lagunas‐Rangel

Experimental Hematology, Journal Year: 2024, Volume and Issue: 132, P. 104172 - 104172

Published: Feb. 2, 2024

Language: Английский

Citations

2
Role of circular RNAs in DNA repair DOI Creative Commons
Francisco Alejandro Lagunas‐Rangel

RNA Biology, Journal Year: 2024, Volume and Issue: 21(1), P. 149 - 161

Published: Nov. 17, 2024

Circular RNAs (circRNAs) exhibit a wide range of activities that allow them to participate in numerous cellular processes and make relevant variety diseases. In this regard, key process which circRNAs are involved, is the focus article, DNA damage repair (DDR). This study aims illustrate how influence different pathways, with particular emphasis on underlying mechanisms. addition, potential medical applications knowledge discussed, particularly diagnosis, prognosis treatment sense, were found play crucial role by regulating expression activity proteins involved various pathways. They interacting their mRNAs, sponging miRNAs target these transcription factors bind promoters, modulating upstream signalling affecting mRNA translation. Furthermore, regulate directly them, sequestering specific compartments controlling activation or DDR signalling.

Language: Английский

Citations

2
How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia DOI Open Access
Tobias R. Haage, Burkhart Schraven, Dimitrios Mougiakakos

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(11), P. 2991 - 2991

Published: May 30, 2023

Mutations of the FLT3 gene are among most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, specific sites FLT3-ITD insertion within show marked heterogeneity regarding both biological clinical features. In contrast to assumption that ITD (IS) restricted juxtamembrane domain (JMD) FLT3, 30% mutations insert at non-JMD level, thereby integrating into various segments tyrosine kinase subdomain 1 (TKD1). ITDs inserted TKD1 have been shown be associated with inferior complete remission rates well shorter relapse-free overall survival. Furthermore, resistance chemotherapy inhibition (TKI) is linked IS. Although general already recognized a negative prognostic marker currently used risk stratification guidelines, even worse impact non-JMD-inserting has not yet particularly considered. Recently, molecular assessment TKI highlighted pivotal role activated WEE1 ITDs. Overcoming therapy FLT3-ITD-mutated may lead more effective genotype- patient-specific treatment approaches.

Language: Английский

Citations

6
Targeting chemoresistance and mitochondria-dependent metabolic reprogramming in acute myeloid leukemia DOI Creative Commons
Lili Feng,

Philip Y Zhang,

Wenda Gao

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Sept. 7, 2023

Chemoresistance often complicates the management of cancer, as noted in instance acute myeloid leukemia (AML). Mitochondrial function is considered important for viability AML blasts and appears to also modulate chemoresistance. As mitochondrial metabolism aberrant AML, any distinct pathways could be directly targeted impact both cell Therefore, identifying targeting those precise rogue elements a valid therapeutic strategy leukemia. Here, we review evidence abnormalities mitochondria metabolic processes cells, that likely We further address several approaches isocitrate dehydrogenase 2 (IDH2), CD39, nicotinamide phosphoribosyl transferase (NAMPT), electron transport chain (ETC) complex consider roles mesenchymal stromal cells. propose term "mitotherapy" collectively refer such regimens attempt override mitochondria-mediated reprogramming, used by cancer Mounting suggests mitotherapy provide complementary overcome chemoresistance liquid cancers, well solid tumors.

Language: Английский

Citations

4