Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy

Huddle, Brandt C.; Grimley, Edward; Chtcherbinine, Mikhail; Buchman, Cameron D.; Takahashi, Cyrus; Debnath, Bikash; McGonigal, Stacy; Mao, Shuai; Li, Siwei; Felton, Jeremy; Pan, Shu; Sun, Duxin; Neamati, Nouri; Buckanovich, Ronald J.; Hurley, Thomas D.; Larsen, Scott D.

doi:10.1016/j.ejmech.2020.113060

Cited by 12 publications

(4 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on all the analyses mentioned earlier, ALDH1A1 and CFD have been identified as novel therapeutic targets for AML. The crystal structures of the two biomarkers were retrieved from the Protein Data Bank (PDB), which are PDB ID: 7JWW [ 25 ] for ALDH1A1 and PDB ID: 5NAT [ 26 ] for CFD. The FDA-approved drugs for AML treatment were targeted and analyzed to achieve a docking score for determining the most effective drug for each of the biomarkers.…”

Section: Resultsmentioning

confidence: 99%

“…The three-dimensional structures of the complexes were predicted based on the binding properties of each ligand with their cognate proteins. The prognostic biomarkers ((ALDH1A1 (PDB ID: 7JWW [ 25 ]) and CFD (PDB ID: 5NAT [ 26 ])) were taken as model proteins after validation of the hub genes docked with each of the FDA-approved drugs for AML treatment. The three-dimensional structures of the prognostic proteins and FDA-approved drugs were retrieved from the protein data bank (PDB) database and PubChem database, respectively.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA‐Approved List through Molecular Docking and Dynamic Simulation

Alom

Faruqe

Molla

et al. 2023

BioMed Research International

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a blood cancer caused by the abnormal proliferation and differentiation of hematopoietic stem cells in the bone marrow. The actual genetic markers and molecular mechanisms of AML prognosis are unclear till today. This study used bioinformatics approaches for identifying hub genes and pathways associated with AML development to uncover potential molecular mechanisms. The expression profiles of RNA-Seq datasets, GSE68925 and GSE183817, were retrieved from the Gene Expression Omnibus (GEO) database. These two datasets were analyzed by GREIN to obtain differentially expressed genes (DEGs), which were used for performing the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI), and survival analysis. The molecular docking and dynamic simulation were performed to identify the most effective drug/s for AML from the drug list approved by the Food and Drug Administration (FDA). By integrating the two datasets, 238 DEGs were identified as likely to be affected by AML progression. GO enrichment analyses exhibited that the upregulated genes were mainly associated with inflammatory response (BP) and extracellular region (CC). The downregulated DEGs were involved in the T-cell receptor signalling pathway (BP), an integral component of the lumenal side of the endoplasmic reticulum membrane (CC) and peptide antigen binding (MF). The pathway enrichment analysis showed that the upregulated DEGs were mainly associated with the T-cell receptor signalling pathway. Among the top 15 hub genes, the expression levels of ALDH1A1 and CFD were associated with the prognosis of AML. Four FDA-approved drugs were selected, and a top-ranked drug was identified for each biomarker through molecular docking studies. The top-ranked drugs were further confirmed by molecular dynamic simulation that revealed their binding stability and confirmed their stable performance. Therefore, the drug compounds, enasidenib and gilteritinib, can be recommended as the most effective drugs against the ALDH1A1 and CFD proteins, respectively.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA‐Approved List through Molecular Docking and Dynamic Simulation

Alom

Faruqe

Molla

et al. 2023

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…As shown in Figure 1C,D, U251 cells exhibited higher expression of ALDH1A3, compared with normal human astrocytes (NHA) and other GBM cell lines. ALDH1A3 has been reported to play a role in chemoresistance in several types of cancer 18–21 . However, the role of ALDH1A3 on GBM radioresistance remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…ALDH1A3 has been reported to play a role in chemoresistance in several types of cancer. 18 , 19 , 20 , 21 However, the role of ALDH1A3 on GBM radioresistance remains to be elucidated. To explore the potential correlation between ALDH1A3 and radioresistance, we assessed the mRNA expression of ALDH1A3 at different radiation doses and exposure times.…”

Section: Resultsmentioning

confidence: 99%

MiR‐4524b‐5p‐targeting ALDH1A3 attenuates the proliferation and radioresistance of glioblastoma via PI3K/AKT/mTOR signaling

Wang

et al. 2023

CNS Neurosci Ther

View full text Add to dashboard Cite

Increasing evidence has revealed a strong connection between the aldehyde dehydrogenase family member ALDH1A3 and tumorigenesis, therapy resistance, and prognosis in diverse types of cancer. However, the specific miRNA involved in the pathways that regulate ALDH1A3‐mediated glioblastoma (GBM) radioresistance remains to be elucidated. In this study, we demonstrated a high expression of ALDH1A3 in GBM cells, which plays a critical role in their proliferation and radioresistance. We also identified miR‐4524b‐5p, which is downregulated in GBM, as the ALDH1A3 upstream regulator. Overexpression of miR‐4524b‐5p reduced proliferation and radioresistance in GBM cells. Moreover, silencing ALDH1A3 reduced PI3K/AKT/mTOR signaling and glycolytic activity in GBM cells, whereas inhibiting mTOR reversed the radioresistance effects of ALDH1A3 on these cells. In vivo experiments have evidenced that ALDH1A3 silencing and miR‐4524b‐5p overexpression significantly reduced tumor growth and GBM cells radioresistance. In summary, targeting the miR‐4524b‐5p and ALDH1A3 axis is a promising therapeutic strategy for treating GBM.

show abstract

Frizzled 6 endows high‐grade serous ovarian cancer with stem‐like properties and chemoresistance

Chen,

Yang,

Shi

et al. 2024

Molecular Carcinogenesis

View full text Add to dashboard Cite

Stem‐like properties contribute to tumor growth, metastasis, and chemoresistance. High‐grade serous ovarian cancer (HGSOC) exhibits a very aggressive phenotype characterized by extensive metastasis, rapid progression, and therapy resistance. Frizzled 6 (FZD6) is overexpressed in HGSOC, and higher levels of FZD6 have been associated with shorter survival times in patients with HGSOC. Functionally, FZD6 promotes HGSOC growth and peritoneal metastasis. It endues HGSOC cells with stem‐like properties by modulating POU5F1, ALDH1, and EPCAM. It can also desensitize HGSOC cells to certain chemical drugs. As a putative ligand for FZD6, WNT7B is also implicated in cell proliferation, stem‐like properties, invasion and migration, and chemoresistance. SMAD7 is a downstream component of FZD6 signaling that is thought to mediate FZD6‐associated phenotypes, at least in part. Therefore, FZD6/WNT7B‐SMAD7 can be considered a tumor‐promoting signaling pathway in HGSOC that may be responsible for tumor growth, peritoneal metastasis, and chemoresistance.

show abstract

Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy

Cited by 12 publications

References 72 publications

Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA‐Approved List through Molecular Docking and Dynamic Simulation

Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA‐Approved List through Molecular Docking and Dynamic Simulation

MiR‐4524b‐5p‐targeting ALDH1A3 attenuates the proliferation and radioresistance of glioblastoma via PI3K/AKT/mTOR signaling

Frizzled 6 endows high‐grade serous ovarian cancer with stem‐like properties and chemoresistance

Contact Info

Product

Resources

About