2. Academic Validation
  3. Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer

Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer

  • J Med Chem. 2023 Feb 9;66(3):1990-2019. doi: 10.1021/acs.jmedchem.2c01769.
Joyeeta Roy 1,  Armita Kyani 1,  Maha Hanafi 1 2,  Yibin Xu 1,  John Takyi-Williams 1 3,  Duxin Sun 1 3,  Essam Eldin A Osman 1 2,  Nouri Neamati 1
Affiliations

Affiliations

  • 1 Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
  • 3 Pharmaceutical Sciences, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
PMID: 36692906 DOI: 10.1021/acs.jmedchem.2c01769
Abstract

Sigma 2 Receptor (σ2R) is overexpressed in select cancers and is regarded as a biomarker for tumor proliferation. σ2R ligands are emerging as promising theranostics for Cancer and neurodegenerative diseases. Herein, we describe the design and synthesis of a series of novel quinolyl pyrazinamides as selective and potent σ2R ligands that show sub-micromolar potency in pancreatic Cancer cell lines. Compounds 14 (JR1-157) and 17 (JR2-298) bind σ2R with Ki of 47 and 10 nM, respectively. Importantly, compound 14 has an oral bioavailability of 60% and shows significant in vivo efficacy without obvious toxicity in a syngeneic model of pancreatic Cancer. The cytotoxicity of the quinolyl pyrazinamides significantly enhanced in the presence of copper and diminished in the presence of the copper-chelator tetrathiomolybdate. In conclusion, compound 14 is water-soluble, metabolically stable, orally active, and increases the expression of the Autophagy marker LC3B and warrants further development for the treatment of pancreatic Cancer.

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