1. Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer
- Author
-
Shaukath Ara Khanum, B.T. Prabhakar, Shivananda Kandagalla, Ankith Sherapura, Vikas H. Malojirao, Shrinath M Baliga, Y L Ramachandra, Jurica Novak, V. Vigneshwaran, Prabhu Thirusangu, Lakshmi Ranganatha, and B S Sharath
- Subjects
Pharmacology ,Cancer Research ,Programmed cell death ,biology ,Chemistry ,Biochemistry (medical) ,Clinical Biochemistry ,Pharmaceutical Science ,Cell Biology ,medicine.disease ,Hedgehog signaling pathway ,lung cancer ,coumarin ,benzophenone ,JAK2/STAT3 ,apoptosis ,Apoptosis ,medicine ,Cancer research ,biology.protein ,Adenocarcinoma ,Lung cancer ,STAT3 ,Protein kinase B ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3Tyr705 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment.
- Published
- 2021