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 Potential predictors for CDX2 expression loss and mismatch repair deficiency in colorectal cancer

Combined drug treatment inhibits the nuclear localization of HSF1 and

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

POR Potential predictors for CDX2 expression loss and mismatch repair deficiency in colorectal cancer

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

TRAP1 is involved in resistance to anthracyclins. (A) Total cell

Du-Shieng CHIEN, University of Iowa, IA, UI, Department of Pharmaceutics

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

Mitochondrial TRAP1 Confers Transforming Potential to Cells (A and B)

Possible factors responsible for succinate accumulation in the tumor.

Antitumor Agents. 211. Fluorinated 2-Phenyl-4-quinolone Derivatives as Antimitotic Antitumor Agents