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

Abstract

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

“…Moreover, analyses of two mutants of Cys522 (Cys522Ala and Cys522Thr) located in the D2 domain, which is the most important target of multiple VCP inhibitors, during PPA inhibition showed that PPA blocked cell proliferation. In addition, these authors reported that PPA exerted antiproliferative effects on colon cancer (HCT116), cervical cancer (HeLa), and multiple myeloma (RPMI8226) cells and inhibited the growth of HCT116 cells resistant to two other inhibitors (CB-5083 and NMS-873), suggesting that PPA is a good candidate to treat cancer and overcome resistance to other VCP/p97 inhibitors [ 151 ].…”

Conserved L464 in p97 D1–D2 linker is critical for p97 cofactor regulated ATPase activity

“…In recent years, an upsurge in p97 inhibitor development has yielded promising starting points for future therapies. A number of structure-activity relationship studies have been aimed towards tailoring inhibitors to specific p97 functions [49,51,[60][61][62]77]. We found that L464 is critical for determining the functionality of p97 inhibitors.…”

“…Because p97 plays a vital role in protein quality control, much has been done in recent years to target p97 with potent and specific inhibitors for potential cancer therapy [16,[54][55][56]. These compounds are divided into two major classes: ATP-competitive inhibitors [57,58] and noncompetitive inhibitors [59][60][61]. We previously evaluated the domain and cofactor-complex selectivity of these compounds, finding that communication between the D1 and D2 domains changes the ability of each inhibitor to affect ATPase activity [24,51,62].…”

The Cure VCP Scientific Conference 2021: Molecular and clinical insights into neurodegeneration and myopathy linked to multisystem proteinopathy-1 (MSP-1)

“…Dr. Chou’s group has been interested in finding covalent inhibitors for VCP that may be more potent in treating CB-5083-resistant cancers. They identified the covalent inhibitor, PPA (ACJI-99C) which modifies Cys 522 at the active site and shows inhibitory activity against human VCP, but not the yeast homolog Cdc48 ( Zhang et al, 2021 ). In parallel, the group has also been characterizing VCP mutations (N660K, E470K) in cancers that are resistant to CB-5083.…”