Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer

Wang, Xueyuan; Bai, Enhe; Zhou, Hui; Sha, Sijia; Miao, Hang; Qin, Yanru; Liu, Zhaogang; Wang, Jia; Zhang, Haoyang; Meng, Lei; Liu, Jia; Hai, Ou; Zhu, Yongqiang

doi:10.1016/j.bmc.2018.12.036

Cited by 13 publications

(14 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some of these derivatives were tested on colon cancer cell lines (HTC-116) and showed antiproliferative activity [ 147 ]. In 2019, Wang et al designed, synthesized and evaluated a new series of VCP/p97 pyrimidine inhibitors and identified that the compound N-(1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl −1H-indol-4-yl)methanesulfonamide exerted a good antiproliferative effect on non-small cell lung cancer cells (A459) and showed good liver stability in mice, dogs and humans [ 148 ]. Very recently, new VCP pyrimidine inhibitors were designed, synthesized and biologically evaluated, and the compound (3-(((2-(2-methyl-4-(methylsulfonamido)-1H-indol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)methyl)phenyl)boronic acid) showed good enzymatic activity [ 149 ].…”

Section: Inhibitors Of Vcpmentioning

confidence: 99%

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Costantini

Capone

Polo

et al. 2021

IJMS

View full text Add to dashboard Cite

Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors.

show abstract

Section: Inhibitors Of Vcpmentioning

confidence: 99%

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Costantini

Capone

Polo

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…For example, VCP upregulation has been associated with unfavorable clinical outcomes in breast cancer patients, and was found to be involved in cell growth and survival in colorectal cancer [43]. In other malignancies in the lung, prostate and pancreas, the VCP expression level was correlated with recurrence rate and prognosis in the patients [44]. Interestingly, although the aberrant expression of VCP has been shown to contribute to cancer progression at different stages, the role of VCP in the pathogenesis of cancers appears controversial.…”

Section: The Aberrant Expression Of Vcp Mediates Er and Mitochondria Dysfunctions In The Progress Of Various Cancersmentioning

confidence: 99%

“…However, the clinical trial of CB-5083 failed due to its toxicities. Some new compounds that may have better potential effects are being investigated, like the VCP inhibitor compound 35, in non-small cell lung cancer [44].…”

Section: The Aberrant Expression Of Vcp Mediates Er and Mitochondria Dysfunctions In The Progress Of Various Cancersmentioning

confidence: 99%

Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases

Sun

Qiu

2020

IJMS

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin–proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders.

show abstract

“…As a targetable enzyme instrumental for protein quality control, VCP has drawn considerable therapeutic attention in many disease areas including cancer. Multiple pharmacological inhibitors targeting the ATPase activity of VCP have been generated including the allosteric inhibitor NMS-873 used in this study and demonstrated promising proof-of-concept anticancer effects in different preclinical models [44,45,[61][62][63]. Excitingly, a highly potent and selective ATP-competitive VCP inhibitor named CB-5339 is currently being evaluated in phase I clinical trials for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and is anticipated to enter clinical testing for solid tumors as well.…”

Section: Discussionmentioning

confidence: 99%

Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor

Wang

Vij

et al. 2021

Cancers

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) patients have a dismal prognosis due in large part to chemotherapy resistance. However, a small subset containing defects in the DNA damage response (DDR) pathways are chemotherapy-sensitive. Identifying intrinsic and therapeutically inducible DDR defects can improve precision and efficacy of chemotherapies for PDAC. DNA repair requires dynamic reorganization of chromatin-associated proteins, which is orchestrated by the AAA+ ATPase VCP. We recently discovered that the DDR function of VCP is selectively activated by Ser784 phosphorylation. In this paper, we show that pSer784-VCP but not total VCP levels in primary PDAC tumors negatively correlate with patient survival. In PDAC cell lines, different pSer784-VCP levels are induced by genotoxic chemotherapy agents and positively correlate with genome stability and cell survival. Causal effects of pSer784-VCP on DNA repair and cell survival were confirmed using VCP knockdown and functional rescue. Importantly, DNA damage-induced pSer784-VCP rather than total VCP levels in PDAC cell lines predict their chemotherapy response and chemo-sensitizing ability of selective VCP inhibitor NMS-873. Therefore, pSer784-VCP drives genotoxic chemotherapy resistance of PDAC, and can potentially be used as a predictive biomarker as well as a sensitizing target to enhance the chemotherapy response of PDAC.

show abstract

Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer

Cited by 13 publications

References 31 publications

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases

Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor

Contact Info

Product

Resources

About