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Novel p97/VCP Inhibitor Induces Endoplasmic Reticulum Stress and Apoptosis in Both Bortezomib-Sensitive and -Resistant Multiple Myeloma Cells

Novel p97/VCP Inhibitor Induces Endoplasmic Reticulum Stress and Apoptosis in Both Bortezomib-Sensitive and -Resistant Multiple Myeloma Cells

Nao Nishimura, Mohamed O Radwan, Masayuki Amano, Shinya Endo, Eri Fujii, Hironori Hayashi, Shikiko Ueno, Niina Ueno, Hiro Tatetsu, Hiroyuki Hata, Yoshinari Okamoto, Masami Otsuka, Hiroaki Mitsuya, Masao Matsuoka, etc.

Cancer Sci. 2019 Oct;110(10):3275-3287.

PMID: 31368616

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42410914	p97 ATPase Activity Inhibitor, DBeQ			Price
IAR4242996	DBeQ			Price

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