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

Giri R. Gnawali, Koichi Okumura, Karolina Perez, Rosa Gallagher, Julia Wulfkuhle, Emanuel F. Petricoin, Sathish Kumar Reddy Padi, Jeremiah Bearss, Zhiyong He, Wei Wang, Andrew S. Kraft

Research output: Contribution to journalArticlepeer-review


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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)1154-1175
Number of pages22
JournalMedicinal Chemistry Research
Issue number7
StatePublished - Jul 2022


  • Antitumor activity
  • Pim kinase
  • Quinoline derivatives
  • mTORC

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry


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