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.

POR Case Report: Brainstem angiocentric glioma presenting in a toddler child–diagnostic and therapeutic challenges

TRAP1 Binds to ETC Complexes IV and II (A) Blue native gel

Lkb1 (Qiagen), Bioz

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

POR CVM-1118 (foslinanib), a 2-phenyl-4-quinolone derivative, promotes apoptosis and inhibits vasculogenic mimicry via targeting TRAP1

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

1) Tumor microenvironment and VM: TAFs (tumor-associated fibroblasts)

Loss of LKB1 promotes enhanced glucose and glutamine metabolism. (A)

2-Phenylquinolin-4-ol, C15H11NO