A preclinical report of a cobimetinib-inspired novel anticancer small-molecule scaffold of isoflavones, NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple cancers

Bashir Lawal; Wen-Cheng Lo; Ntlotlang Mokgautsi; Maryam Rachmawati Sumitra; Harshita Khedkar; Alexander Th Wu; Hsu-Shan Huang

A preclinical report of a cobimetinib-inspired novel anticancer small-molecule scaffold of isoflavones, NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple cancers

Am J Cancer Res. 2021 Jun 15;11(6):2590-2617. eCollection 2021.

Authors

Bashir Lawal^{1

2}, Wen-Cheng Lo^{3

4

5}, Ntlotlang Mokgautsi^{1

2}, Maryam Rachmawati Sumitra^{1

2}, Harshita Khedkar^{1

2}, Alexander Th Wu^{6

7

8

9}, Hsu-Shan Huang^{1

2

10

11}

Affiliations

¹ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica Taipei 11031, Taiwan.
² Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
³ Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁴ Department of Neurosurgery, Taipei Medical University Hospital Taipei 11031, Taiwan.
⁵ Taipei Neuroscience Institute, Taipei Medical University Taipei 11031, Taiwan.
⁶ TMU Research Center of Cancer Translational Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁷ The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
⁸ Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University Taipei 11031, Taiwan.
⁹ Graduate Institute of Medical Sciences, National Defense Medical Center Taipei 11490, Taiwan.
¹⁰ School of Pharmacy, National Defense Medical Center Taipei 11490, Taiwan.
¹¹ PhD Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University Taipei 11031, Taiwan.

PMID: 34249417
PMCID: PMC8263676

Abstract

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways are critical for normal human physiology, and any alteration in their regulation leads to several human cancers. These pathways are well interconnected and share a survival mechanism for escaping the depressant effect of antagonists. Therefore, novel small molecules capable of targeting both pathways with minimal or no toxicity are better alternatives to current drugs, which are disadvantaged by their accompanying resistance and toxicity. In this study, we demonstrate that the PI3K/AKT/mTOR/MEK is a crucial oncoimmune signature in multiple cancers. Moreover, we describe NSC777213, a novel isoflavone core and cobimetinib-inspired small molecule, which exhibit both antiproliferative activities against all panels of NCI60 human tumor cell lines (except COLO205 and HT29) and a selective cytotoxic preference for melanoma, non-small-cell lung cancer (NSCLC), brain, renal, and ovarian cancer cell lines. Notably, for NSC777213 treatment, chemoresistant ovarian cancer cell lines, including SK-OV-3, OVCAR-3, OVCAR-4, and NCI/ADR-RES, exhibited a higher antiproliferative sensitivity (total growth inhibition (TGI) = 7.62-31.50 µM) than did the parental cell lines OVCAR-8 and IGROV1 (TGI > 100 µM). NSC777213 had a mechanistic correlation with clinical inhibitors of PI3K/AKT/mTOR/MEK. NSC777213 demonstrates robust binding interactions and higher affinities for AKT and mTOR than did isoflavone, and also demonstrate a higher affinity for human MEK-1 kinase than some MEK inhibitors under clinical developments. In addition, treatment of U251 and U87MG cells with NSC777213 significantly downregulated the expression levels of the total and phosphorylated forms of PI3K/AKT/mTOR/MEK. Our study suggests that NSC777213 is a promising PI3K/AKT/mTOR/MEK inhibitor for further preclinical and clinical evaluation as a chemotherapeutic agent, particularly for the treatment of NSCLC, melanoma, and brain, renal, and ovarian cancers.

Keywords: NCI60 human tumor cell lines; NSC777213; PI3K/AKT/mTOR-MEK pathways; anticancer activities; immune infiltrations; molecular docking simulations.