Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Alverez, Celeste; Bulfer, Stacie L.; Chakrasali, R. T.; Chimenti, Michael S.; Deshaies, Raymond J.; Green, Neal; LaPorte, Matthew G.; Lewis, Taber S.; Liang, Mary; Moore, William; Neitz, R. Jeffrey; Peshkov, Vsevolod A.; Walters, Michael A.; Zhang, Feng; Arkin, Michelle R.; Wipf, Peter; Huryn, Donna M.

doi:10.1021/acsmedchemlett.5b00396

Cited by 30 publications

(29 citation statements)

References 22 publications

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“…Several groups have recently developed specific inhibitors against VCP (Alverez et al, 2015(Alverez et al, , 2016Bursavich et al, 2010;Chou et al, 2010Chou et al, , 2011Chou et al, , 2013Chou et al, , 2014Fang et al, 2015;Gui et al, 2016;Magnaghi et al, 2013;Polucci et al, 2013;Wijeratne et al, 2016), these efforts were reviewed and summarized elsewhere (Chapman et al, 2015). Among these specific inhibitors, DBeQ was initially developed as a reversible inhibitor of VCP/p97 that compromises protein homeostasis through impairment of both ubiquitin proteasome system (UPS) and autophagic protein clearance.…”

Section: Introductionmentioning

confidence: 99%

VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

et al. 2016

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Abbreviations: AAA-ATPase, ATPase associated with diverse cellular activities; BRCA1/2, breast cancer 1/2; PARP1, poly ADP-ribose polymerase-1; DBeQ, N 2 ,N 4 -dibenzylquinazoline-2,4-diamine; PBS, phosphate buffered saline; EGF, epidermal growth factor; TBS, tris-buffered saline; PERK, protein kinase R-like endoplasmic reticulum kinase; TCGA, the Cancer Genome Atlas; PVDF, polyvinylidene difluoride; IRE1a, inositol-requiring enzyme 1 alpha; CHOP, CCAAT/enhancer-binding protein homologous protein; ATF4, activating transcription factor 4; eIF2a, eukaryotic initiation factor 2 alpha; BiP, binding immunoglobulin protein; Grp78, glucose regulated protein 78; GADD34, growth arrest And DNA-damage-inducible 34.

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Section: Introductionmentioning

confidence: 99%

VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

et al. 2016

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“…A number of VCP inhibitors have been reported including quinazolines, such as ML240, which have been shown to be ATP‐competitive inhibitors, and CB‐5083, which recently entered Phase I cancer clinical trials ,. In addition, NMS‐873 and SMDC818909 have been reported to be allosteric inhibitors of VCP, and the natural products withaferin A and xanthohumol were also identified as potent VCP inhibitors. Increased levels of VCP in cancer cells have been reported to be associated with poor clinical outcomes .…”

Section: Resultsmentioning

confidence: 99%

Valosin‐containing Protein is a Target of 5′‐l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells

et al. 2016

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Fuligocandin B (2) is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B (2) and its derivative 5′‐I fuligocandin B (4), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5′‐I fuligocandin B (4), and employed a pull‐down assay to identify valosin‐containing protein (VCP/p97), an AAA ATPase, as a 5′‐I fuligocandin B (4) target protein. Knock‐down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, 4 enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by 4 increases CHOP‐mediated DR5 up‐regulation, which enhances TRAIL‐induced cell death in AGS cells. To the best of our knowledge, this is the first example to show a relationship between VCP and TRAIL‐resistance‐overcoming activity in cancer cells.

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“…3 p97 has been recognized as a potential target for treating cancer as well as neurodegeneration,4 ,5 thus triggering drug discovery efforts in both industry and academia. 6,7,8, 9,10 …”

Section: Introductionmentioning

confidence: 99%

A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site

et al. 2017

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The turnstile motion of two neighboring threonines sets up a dynamic side chain interplay that can accommodate both polar and apolar ligands in a small molecule allosteric protein binding site. A computational model based on SAR data and both X-ray and cryo-EM structures of the AAA ATPase p97 was used to analyze the effects of paired threonines at the inhibitor site. Specifically, the Thr side chain hydroxyl groups form a hydrogen bonding network that readily accommodates small, highly polar ligand substituents. Conversely, diametric rotation of the χ1 torsion by 150–180° orients the side chain β-methyl groups into the binding cleft, creating a hydrophobic pocket that can accommodate small, apolar substituents. This motif was found to be critical for rationalizing the affinities of a structurally focused set of inhibitors of p97 covering a >2,000-fold variation in potencies, with a preference for either small-highly polar or small-apolar groups. The threonine turnstile motif was further validated by a PDB search that identified analogous binding modes in ligand interactions in PKB, as well as by an analysis of NMR structures demonstrating additional gear-like interactions between adjacent Thr pairs. Combined, these data suggest that the threonine turnstile motif may be a general feature of interest in protein binding pockets.

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Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Cited by 30 publications

References 22 publications

VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

Valosin‐containing Protein is a Target of 5′‐l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells

A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site

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