POR CVM-1118 (foslinanib), a 2-phenyl-4-quinolone derivative

CVM-1118 (foslinanib) is a phosphoric ester compound selected from 2-phenyl-4-quinolone derivatives. The NCI 60 cancer panel screening showed CVM-1125, the major active metabolite of CVM-1118, to exhibit growth inhibitory and cytotoxic effects at nanomolar range. CVM-1118 possesses multiple bioactivities, including inducing cellular apoptosis, cell cycle arrest at G2/M, as well as inhibiting vasculogenic mimicry (VM) formation. The TNF receptor associated protein 1 (TRAP1) was identified as the binding target of CVM-1125 using nematic protein organization technique (NPOT) interactome analysis. Further studies demonstrated CVM-1125 reduced the protein level of TRAP1 and impeded its downstream signaling by reduction of cellular succinate levels and destabilization of HIF-1α. The pharmacogenomic biomarkers associated with CVM-1118 were also examined by Whole Genome CRISPR Knock-Out Screening. Two hits (STK11 and NF2) were confirmed with higher sensitivity to the drug in cell knock-down experiments. Biological assays indicate that the mechanism of action of CVM-1118 is via targeting TRAP1 to induce mitochondrial apoptosis, suppress tumor cell growth, and inhibit vasculogenic mimicry formation. Most importantly, the loss-of-function mutations of STK11 and NF2 are potential biomarkers of CVM-1118 which can be applied in the selection of cancer patients for CVM-1118 treatment. CVM-1118 is currently in its Phase 2a clinical development.

Full article: Developing our knowledge of the quinolone scaffold and its value to anticancer drug design

Richard E. B. Seftor's research works Shepherd University, Shepherdstown and other places

Nematic protein organisation technique (NPOT) for interactome analysis

Lkb1 (Qiagen), Bioz

Most frequently comutated genes with STK11 in non-small cell lung

Frontiers The development of cancers research based on mitochondrial heat shock protein 90

4-Hydroxy-2-quinolones: syntheses, reactions and fused heterocycles

Li-Chen Chou's research works China Medical University (ROC), Taichung and other places

2-Phenylquinolin-4-ol, C15H11NO