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DRUG:

WZ4002

i
Other names: WZ4002
Company:
Dana-Farber Cancer Institute
Drug class:
EGFR inhibitor
Related drugs:
2ms
Repurposing Non-Nucleosidic Reverse Transcriptase Inhibitors (NNRTIs) to Overcome EGFR T790M-Mediated Acquired Resistance in Non-Small Cell Lung Cancer. (PubMed, J Cell Biochem)
This study investigates the repurposing potential of non-nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non-small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of -7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002...Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC50 value of 54.22 nM and spared the wild-type EGFR TK with an IC50 of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations.
Preclinical • Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR L858R • EGFR T790M • EGFR wild-type • EGFR L858R + EGFR T790M • EGFR H1975
|
Tagrisso (osimertinib) • WZ4002
4ms
Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. (PubMed, Int J Mol Sci)
We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients.
Journal
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2)
|
WZ4002
1year
ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors. (PubMed, Cancer Metab)
Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo.
Preclinical • Journal
|
CCND1 (Cyclin D1) • PKM (Pyruvate Kinase M1/2)
|
Xalkori (crizotinib) • WZ4002 • KU-55933
3years
Non-Canonical Role of PDK1 as a Negative Regulator of Apoptosis through Macromolecular Complexes Assembly at the ER-Mitochondria Interface in Oncogene-Driven NSCLC. (PubMed, Cancers (Basel))
H1993 and H1975 cells were stably transfected with scrambled (shCTRL) or PDK1-targeted (shPDK1) shRNA and then treated with MET inhibitor crizotinib (1 µM), double mutant EGFR inhibitor WZ4002 (1 µM) or vehicle for 48 h. The effects of PDK1 knockdown on glucose metabolism and apoptosis were evaluated in untreated and TKI-treated cells. Co-immunoprecipitation studies showed that PDK1 interacts with PKM2, Bcl-2 and Bcl-xL, forming macromolecular complexes at the ER-mitochondria interface. Our findings showed that downregulation of PDK1 is able to potentiate the effects of TKIs through the disruption of macromolecular complexes involving PKM2, Bcl-2 and Bcl-xL.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • PDPK1 (3-Phosphoinositide dependent protein kinase 1) • PKM (Pyruvate Kinase M1/2)
|
EGFR mutation • EGFR H1975
|
Xalkori (crizotinib) • WZ4002
3years
Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC). (PubMed, Bioorg Chem)
To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed...Among them, compounds 2i (IC 0.171 µM) and 11h (IC 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay...The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.
Journal
|
EGFR (Epidermal growth factor receptor)
|
EGFR mutation • EGFR L858R • EGFR T790M • EGFR L858R + EGFR T790M • EGFR H1975
|
Gilotrif (afatinib) • gefitinib • Vizimpro (dacomitinib) • WZ4002
almost4years
Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines. (PubMed, Cells)
We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.
Preclinical • Journal
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EGFR (Epidermal growth factor receptor) • VIM (Vimentin) • CDK7 (Cyclin Dependent Kinase 7)
|
EGFR H1975 • VIM expression
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Tagrisso (osimertinib) • WZ4002