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.
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Acknowledgements
Ankith Sherapura thankful to the Lady Tata Memorial Trust for JRS (2020–2021) and B.T. Prabhakar gratefully acknowledge the grant support by VGST (VGST/P-2/CISEE/GRD-231/2013–14) and SERB [EMR/2017/00088/ dated 3/01/2019]. Shaukath Ara Khanum thankfully acknowledges the financial support provided by VGST, Bangalore, under CISEE Program [Project Sanction Order No. VGST/CISEE/282/2012-13].
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AS performed all the experiments, VHM, TP, VV assisted in experimental setup, and S.B.S, S.K, JN supported through in-silico approach, LR for synthesis of drug, SB, for scientific discussion and SAK and PBT designed the experiments, wrote the manuscript and monitored the entire investigation.
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Sherapura, A., Malojirao, V.H., Thirusangu, P. et al. Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer. Apoptosis 27, 49–69 (2022). https://doi.org/10.1007/s10495-021-01699-5
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DOI: https://doi.org/10.1007/s10495-021-01699-5