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.

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

POR Tumor subtypes and signature model construction based on chromatin regulators for better prediction of prognosis in uveal melanoma

2-Phenylquinolin-4-ol, C15H11NO

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)

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

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells. - Abstract - Europe PMC

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

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells. - Abstract - Europe PMC

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

2-Phenylquinolin-4-ol, C15H11NO

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

Synthesis and Preclinical Evaluations of 2-(2 -Fluorophenyl)-6,7-methylenedioxyquinolin-4-one Monosodium Phosphate (CHM-1−P-Na) as a Potent Antitumor Agent