scholarly journals Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

RSC Advances ◽  
2018 ◽  
Vol 8 (30) ◽  
pp. 16470-16493 ◽  
Author(s):  
Muhammad Latif ◽  
Zaman Ashraf ◽  
Sulman Basit ◽  
Abdul Ghaffar ◽  
Muhammad Sohail Zafar ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma ◽  
Orally Bioavailable

This review describes hit-to-drug evolution milestones, synthetic strategies and clinical significance of novel DAAPalogues discovered for ALK inhibition which are either progressing as investigational or preclinical candidates to treat the patients with ALK+-NSCLC.

Discovery of anaplastic lymphoma kinase inhibitors from natural product library: A holistic in silico approach

2020 ◽  
Author(s):  
Saranyadevi Subburaj ◽  
Tanvi Anand Nagrale ◽  
Mohd. Mustufa Khan ◽  
Nivya James ◽  
Ramanathan Karuppasamy ◽  
...  
Keyword(s):  
Natural Product ◽  
Anaplastic Lymphoma Kinase ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Anaplastic Lymphoma ◽  
Natural Product Library

Discovery of novel anaplastic lymphoma kinase inhibitors: Structure and energy-based pharmacophore strategy

2019 ◽  
Vol 18 (03) ◽  
pp. 1950014 ◽  
Author(s):  
Nivya James ◽  
V. Shanthi ◽  
K. Ramanathan
Keyword(s):  
Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Density Functional ◽  
Kinase Inhibitors ◽  
Chemical Reactivity ◽  
Pharmacophore Model ◽  
Density Functional Theory Calculations ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Glide Docking

The clinical outcomes in patients with non-small cell lung cancer have improved, as a result of anaplastic lymphoma kinase (ALK) inhibition. Therefore in the current study, substantial effort has been made to identify ALK inhibitors through systematic virtual screening experiment consisting of e-pharmacophore and pharmacophore perception techniques. Initially, a pharmacophore model (AAAHP.193) and an e-pharmacophore model (DDRRR) encompassing the whole dataset of 12 known ALK inhibitors were developed. The hypotheses could retrieve effective compounds from DrugBank database (8621 molecules), which were then subjected to molecular docking and ADME prediction. These approaches resulted in the identification of five hits, namely, nebivolol, HDY, D42, 796, and LZE having higher Glide docking scores and promising ADME properties with augmented CNS involvement. Moreover, molecular dynamics simulations were performed to validate the inhibitory activity of the hit compounds, and density functional theory calculations were carried out to scrutinize the chemical reactivity of the hits. Subsequent interaction and scaffold analysis identified prominent interactions of the hits with ALK kinase domain and scaffolds with anti-tumor activity against lung cancer cell lines. We strongly believe that the study provides an outlook for the sighting of novel and potent ALK inhibitors in the near future.

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