2. Academic Validation
  3. The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

  • Biomolecules. 2019 Dec 13;9(12):875. doi: 10.3390/biom9120875.
Jong Hyun Lee 1,  Chakrabhavi Dhananjaya Mohan 2,  Salundi Basappa 3,  Shobith Rangappa 4,  Arunachalam Chinnathambi 5,  Tahani Awad Alahmadi 5 6,  Sulaiman Ali Alharbi 5,  Alan Prem Kumar 7 8,  Gautam Sethi 8,  Kwang Seok Ahn 1,  Kanchugarakoppal S Rangappa 9
Affiliations

Affiliations

  • 1 College of Korean Medicine, Kyung Hee University, #47, Kyungheedae-gil, Dongdaemoon-gu, Seoul 130-701, Korea.
  • 2 Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
  • 3 Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
  • 4 Adichunchanagiri Institute for Molecular Medicine, BG Nagara-571448, Nagamangala Taluk, Mandya District 571448, India.
  • 5 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
  • 6 Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University Medical City, Riyadh 11461, Saudi Arabia.
  • 7 Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
  • 8 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
  • 9 Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India.
PMID: 31847229 DOI: 10.3390/biom9120875
Abstract

STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung Cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream Protein Tyrosine Kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of Caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xL, and Survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

Keywords

ACHP; NSCLC; STAT3 signaling inhibitor; cytotoxicity.

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