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Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer

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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Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information Files).

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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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Correspondence to Shaukath Ara Khanum or B. T. Prabhakar.

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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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Keywords

  • Lung cancer
  • Coumarin
  • Benzophenone
  • JAK2/STAT3
  • Apoptosis