Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells

Abstract

p97/VCP is an endoplasmic reticulum (ER)‐associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50, 100‐500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of DBeQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell‐free ATPase assays, OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition.

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

“…Before the docking simulations, PT5 and 1IEP preparation included the addition of hydrogens, the assignment of bond order, and assessment of the correct protonation as previously described [46,47]. The MOE 2019.01 software (Chemical Computing Group, Montreal, Canada) was employed for the preparation, interactive docking, visualization and the analysis procedures using its default parameters [48,49,50].…”

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

“…CHOP is an important transcription factor involved in regulating apoptosis and drug sensitivity [168][169][170]. Studies have shown that the levels of CHOP mRNA and its protein level were significantly lower in lung cancer tissues compared with noncancerous tissues.…”

A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells

“…13 C spectra are referenced to residual CDCl 3 (77.2). 19 F NMR spectra were recorded on a Varian 300 (at 282 MHz) and are reported relative to CFCl 3 (δ 0.0). Data for 1 H and 19 F NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration).…”

“…The ATP-competitive inhibitor DBeQ (N 2 , N 4 -Dibenzylquinazoline-2,4-diamine) mainly targets the D2 domain. DBeQ blocks many biological processes, including degradation of ubiquitin-fusion degradation and ERAD pathway substrates, as well as autophagosome maturation [19][20][21]. Two DBeQ derivatives with IC 50 values of ~100 nM, ML240 and ML241, have been developed.…”