Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer.
Matthew G LaPorteCeleste AlverezAlexander ChatterleyMarina KovaliovEvan J CarderMichael J HoughtonChaemin LimEric R MillerLalith P SamankumaraMary LiangKaylan KerriganZhizhou YueShan LiFrancesca TomainoFeng WangNeal GreenGordon M StottApurva SrivastavaTsui-Fen ChouPeter WipfDonna M HurynPublished in: ACS medicinal chemistry letters (2023)
The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound ( R )- 29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.
Keyphrases
- cancer therapy
- small molecule
- protein protein
- cell death
- papillary thyroid
- oxidative stress
- drug delivery
- diffuse large b cell lymphoma
- endoplasmic reticulum stress
- amino acid
- binding protein
- cell therapy
- cell cycle arrest
- induced apoptosis
- squamous cell carcinoma
- stem cells
- combination therapy
- cell proliferation
- bone marrow
- bioinformatics analysis