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

Ankith Sherapura¹, Vikas H Malojirao^{1

2}, Prabhu Thirusangu^{1

3}, B S Sharath⁴, Shivananda Kandagalla⁵, V Vigneshwaran^{1

6}, Jurica Novak⁵, Lakshmi Ranganatha⁷, Y L Ramachandra⁸, Shrinath M Baliga⁹, Shaukath Ara Khanum¹⁰, B T Prabhakar¹¹

Affiliations

¹ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India.
² Division for DNA Repair Research, Department of Neurosurgery, Centre for Neuroregeneration, Houston Methodist, Fannin Street, Houston, TX, USA.
³ Department of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ School of System Biomedical Science and Department of Bioinformatics and Lifescience, Soongsil University, Seoul, South Korea.
⁵ Laboratory of Computational Modelling of Drugs, Higher Medical and Biological School, South Ural State University, Chaikovskogo 20A, Chelyabinsk, Russia, 454008.
⁶ Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, 60612, USA.
⁷ Department of Chemistry, The National Institute of Engineering, Mysuru, Karnataka, 570008, India.
⁸ Department of Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnanasahyadri, Shankaraghatta, 577 451, India.
⁹ Department of Radiation Oncology, Mangalore Institute of Oncology, Mangalore, Karnataka, 575 002, India.
¹⁰ Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, Karnataka, 570 005, India. shukathara@yahoo.co.in.
¹¹ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India. prabhakarbt@gmail.com.

PMID: 34837562
DOI: 10.1007/s10495-021-01699-5

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

Ankith Sherapura et al. Apoptosis. 2022 Feb.

. 2022 Feb;27(1-2):49-69.

doi: 10.1007/s10495-021-01699-5. Epub 2021 Nov 27.

Authors

Affiliations

¹ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India.
² Division for DNA Repair Research, Department of Neurosurgery, Centre for Neuroregeneration, Houston Methodist, Fannin Street, Houston, TX, USA.
³ Department of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ School of System Biomedical Science and Department of Bioinformatics and Lifescience, Soongsil University, Seoul, South Korea.
⁵ Laboratory of Computational Modelling of Drugs, Higher Medical and Biological School, South Ural State University, Chaikovskogo 20A, Chelyabinsk, Russia, 454008.
⁶ Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, 60612, USA.
⁷ Department of Chemistry, The National Institute of Engineering, Mysuru, Karnataka, 570008, India.
⁸ Department of Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnanasahyadri, Shankaraghatta, 577 451, India.
⁹ Department of Radiation Oncology, Mangalore Institute of Oncology, Mangalore, Karnataka, 575 002, India.
¹⁰ Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, Karnataka, 570 005, India. shukathara@yahoo.co.in.
¹¹ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India. prabhakarbt@gmail.com.

PMID: 34837562
DOI: 10.1007/s10495-021-01699-5

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 JAK2^Tyr1007/1008 phosphorylation, and inhibits its downstream STAT3^Tyr705 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.

Keywords: Apoptosis; Benzophenone; Coumarin; JAK2/STAT3; Lung cancer.

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

Affiliations

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

Authors

Affiliations

Abstract

References

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MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous