Free energy perturbation guided Synthesis with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC)

2021 ◽  
pp. 105226
Author(s):  
Kshipra S. Karnik ◽  
Aniket P. Sarkate ◽  
Shailee V. Tiwari ◽  
Rajaram Azad ◽  
Pravin S. Wakte
Keyword(s):  
Lung Cancer ◽  
Free Energy ◽  
Small Cell Lung Cancer ◽  
Small Molecule ◽  
Biological Evaluation ◽  
Small Cell ◽  
Free Energy Perturbation ◽  
Quinoline Derivatives ◽  
Small Cell Lung ◽  
Energy Perturbation

scholarly journals Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Kaili Long ◽  
Lili Gu ◽  
Lulu Li ◽  
Ziyu Zhang ◽  
Enjie Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Small Molecule ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Molecular Compound ◽  
Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

Abstract LB-232: Potent, novel small molecule inhibitors targeting EGFR L858R/T790M mutation for non-small cell lung cancer

2014 ◽  
Author(s):  
Dhanalakshmi Sivanandhan ◽  
Payal K. Parikh ◽  
Avinash Sheshachalam ◽  
Chandregowda V ◽  
Rajagopal Bhakthavatchalam ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Small Molecule ◽  
Cell Lung Cancer ◽  
Small Molecule Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation
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