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Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors

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Abstract

Compound VBT-5445 was identified as an inhibitor to block the association of Pim and the protein Enhancer of Decapping 3 (EDC3), a Pim substrate, which normally functions to enhance the decapping of messenger RNA (mRNA). It was also shown to inhibit both the Pim and mTORC protein kinases. The activity of this compound class can be fine-tuned by structural modification. A series of VBT analogs were designed, synthesized, and evaluated. These compounds decrease the growth of multiple cancer types, including pancreas, prostate, breast, lung, and leukemia. Notably, 6-methyl (GRG-1-31, 6d), 4-chloro (GRG-1-34, 6e), 4-Bromo (GRG-1-35, 6f), and phenylthio substituted (GRG-1-104, 6n) derivatives are highly potent at inhibiting tumor growth. The ability of these compounds to block cancer growth in vitro is highly correlated with their activity as mTORC inhibitors. The toxicity of GRG 1–34 is low in mice treated with twice-daily gavage for 30 days and did not induce weight loss. Pharmacokinetics of a single oral dose demonstrated a peak concentration at 0.5 h after gavage. In summary, further development of this compound class has the potential to inhibit important signaling pathways and impact cancer treatment.

Development of a Dual Pim and mTORC protein kinase inhibitor.

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Acknowledgements

We wish to acknowledge the support of the UACC Analytical Chemistry Shared Resource funded by P30 CA023074 for carrying out the pharmacokinetics experiments and importantly the Arizona Center for Drug Discovery and NIH 5R01GM130772 (WW). Additionally, we wish to acknowledge support from the George Mason University College of Science for the Reverse Phase Protein Array work.

Funding

This work was supported in part by R21CA241010-01A1 to ASK and KO.

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Authors and Affiliations

  1. R. Ken Coit College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1295 N. Martin Ave, Tucson, AZ, 85721, USA

    Giri R. Gnawali, Zhiyong He & Wei Wang

  2. Department of Physiology, University of Arizona College of Medicine, 1501 N. Campbell, Tucson, AZ, 85724, USA

    Koichi Okumura

  3. Department of Medicine, University of Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ, 85724, USA

    Karolina Perez, Jeremiah Bearss & Andrew S. Kraft

  4. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    Rosa Gallagher, Julia Wulfkuhle & Emanuel F. Petricoin

  5. Department of Molecular Biology and Biophysics, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Sathish Kumar Reddy Padi

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  1. Giri R. Gnawali
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  2. Koichi Okumura
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Correspondence to Wei Wang or Andrew S. Kraft.

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This paper is dedicated to Laurence H. Hurley to be published in a special issue of Medicinal Chemistry Research in honor of him.

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Gnawali, G.R., Okumura, K., Perez, K. et al. Synthesis of 2-oxoquinoline derivatives as dual pim and mTORC protein kinase inhibitors. Med Chem Res 31, 1154–1175 (2022). https://doi.org/10.1007/s00044-022-02904-z

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  • DOI: https://doi.org/10.1007/s00044-022-02904-z

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