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

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.

西格玛2型受体（Sigma 2 receptor, σ2R）在特定癌症中过表达，被视为肿瘤增殖的生物标志物。σ2R配体正逐渐成为针对癌症与神经退行性疾病的极具潜力的诊疗剂（theranostics）。本文报道了一系列新型喹啉基烟酰胺类化合物的设计与合成，这类化合物为选择性且高效的σ2R配体，在胰腺癌细胞系中展现出亚微摩尔级的活性。化合物14（JR1-157）与17（JR2-298）与σ2R结合的抑制常数（Ki）分别为47 nM与10 nM。值得关注的是，化合物14的口服生物利用度达60%，在胰腺癌同源移植瘤模型中展现出显著的体内抗肿瘤活性，且未出现明显毒性。该类喹啉基烟酰胺类化合物的细胞毒性在铜离子存在下显著增强，而在铜螯合剂四硫钼酸盐存在下则被显著削弱。综上，化合物14水溶性良好、代谢稳定、具备口服活性，且可上调自噬标志物LC3B的表达，值得进一步开发用于胰腺癌的治疗。