Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Santofimia‐Castaño, Patricia; Xia, Yi; Lan, Wenxian; Zhou, Zhengwei; Huang, Can; Peng, Ling; Soubeyran, Philippe; Velázquez‐Campoy, Adrián; Abián, Olga; Rizzuti, Bruno; Neira, José L.; Iovanna, Juan

doi:10.1172/jci127223

Cited by 77 publications

(106 citation statements)

References 46 publications

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“…The best compound (that with the largest affinity for NUPR1, and within the same order than that of NUPR1 for its natural partners), ZZW-115 ( Fig. 5f), kills different kinds of cancer cells with IC 50 values ranging from 0.84 to 4.93 μM [101]. Most importantly, ZZW-115 shows a dose-dependent tumor regression in xenografted mice, almost leading to tumor disappearance after 30 days of treatment with 5 mg/(kg day), with no apparent neurological effects.…”

Section: The P53 System: a Master Regulator Of Cell Functions With Idmentioning

confidence: 99%

“…Most importantly, ZZW-115 shows a dose-dependent tumor regression in xenografted mice, almost leading to tumor disappearance after 30 days of treatment with 5 mg/(kg day), with no apparent neurological effects. At the cellular level, ZZW-115 induces cell death by both necroptotic [as measured by lactate dehydrogenase (LDH) release] and apoptotic (as measured by caspase 3/7 activity) mechanisms, with a concomitant mitochondrial metabolism failure that triggers lower production of ATP and reactive oxygen species (ROS) overproduction [101]. Importantly, these molecular mechanisms are similar to those observed in NUPR1-deficient cells [102] and can be inhibited by Necrostatin-1 (an inhibitor of necroptosis) and Z-VAD-FMK (an inhibitor of caspases).…”

Section: The P53 System: a Master Regulator Of Cell Functions With Idmentioning

confidence: 99%

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Targeting intrinsically disordered proteins involved in cancer

Santofimia‐Castaño¹,

Rizzuti²,

Xia³

et al. 2019

Cell. Mol. Life Sci.

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Intrinsically disordered proteins (IDPs) do not have a well-defined structure under physiological conditions, but they have key roles in cell signaling and regulation, and they are frequently related to the development of diseases, such as cancer and other malignancies. This has converted IDPs in attractive therapeutic targets; however, targeting IDPs is challenging because of their dynamic nature. In the last years, different experimental and computational approaches, as well as the combination of both, have been explored to identify molecules to target either the hot-spots or the allosteric sites of IDPs. In this review, we summarize recent developments in successful targeting of IDPs, all of which are involved in different cancer types. The strategies used to develop and design (or in one particular example, to repurpose) small molecules targeting IDPs are, in a global sense, similar to those used in well-folded proteins: (1) screening of chemically diverse or target-oriented compound libraries; or (2) study of the interfaces involved in recognition of their natural partners, and design of molecular candidates capable of binding to such binding interface. We describe the outcomes of using these approaches in targeting IDPs involved in cancer, in the view to providing insight, to target IDPs in general. In a broad sense, the designed small molecules seem to target the most hydrophobic regions of the IDPs, hampering macromolecule (DNA or protein)-IDP interactions; furthermore, in most of the molecule-IDP complexes described so far, the protein remains disordered.

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Section: The P53 System: a Master Regulator Of Cell Functions With Idmentioning

confidence: 99%

Section: The P53 System: a Master Regulator Of Cell Functions With Idmentioning

confidence: 99%

Targeting intrinsically disordered proteins involved in cancer

Santofimia‐Castaño¹,

Rizzuti²,

Xia³

et al. 2019

Cell. Mol. Life Sci.

Self Cite

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“…A cell-based assay would also be required to test hits from the screen under in vivo conditions, for example proteins labeled with FRET donors and acceptors, co-immunoprecipitation or indirectly by measuring amounts of HIF1α. Although challenging due to several highly disordered regions in the HIF-1 protein, such screening would be still feasible as recently reported for inhibiting PPI in the cancer-associated and intrinsically disordered protein NUPR1 [148,149].…”

Section: Targeting the Chaperone Role Of Nqo1 To Inactivate Hif-1: Fmentioning

confidence: 99%

Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1

Salido¹,

Timson²,

Betancor-Fernández³

et al. 2020

Preprint

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HIF-1α is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1α inhibition represents an interesting target for anti-cancer therapy. It was recently shown that HIF-1α interaction with NQO1 inhibits its proteasomal degradation, thus suggesting that targeting the stability of NQO1 could led to destabilization of HIF-1α as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1α are beginning to be unraveled, we review here our current knowledge on the intracellular functions and stability of NQO1, its pharmacological modulation by small ligands, and the molecular determinants of its roles as a chaperone of many different proteins including cancer-associated factors such as p53 and p73α. This knowledge is then discussed in the context of potentially targeting the intracellular stability of HIF-1α by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies.

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“…The maintenance of high levels of p-eIF2α in Nupr1 -/acini propose a models where NUPR1 would contribute directly or indirectly to the dephosphorylation of eIF2α as a mechanism to allow restoration of protein translation. To test this model, we examined phosphorylation of eIF2α in response to ER stress response in PANC-1 cells (NUPR1 +/+ ) or NUPR1-null cells (NUPR1 -/-), generated by CRISPR/Cas9 deletion of NUPR1 [29]. Treatment with 1 µM of TPS for up to 24 hours showed NUPR1 -/cells maintained higher levels of p-eIF2α compared to NUPR1 +/+ cells ( Figure 6A Decreased fluorescence was confirmed by two-way ANOVA, which showed an effect of both TPS (p < 0.0001) and NUPR1 (p < 0.0001), as well as an interaction between the two factors (p = 0.001).…”

Section: Nupr1-depletion Enhances Eif2α Phosphorylation and Delays Thmentioning

confidence: 99%

The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2α

Santofimia‐Castaño

Bocchio

et al. 2020

Preprint

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NUPR1 is an 82 amino-acids protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1's well established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely unknown. Here we report that NUPR1 plays a central role during the endoplasmic reticulum stress response. Biochemical analysis revealed a general attenuation of the unfolded protein response in pancreas of mice lacking NUPR1. Ultrastructural analysis of pancreata revealed fewer morphological alteration in tunicamycin-treated Nupr1 -/compared to Nupr1 +/+ . A bioinformatical analysis of potential interacting partners of NUPR1 showed significant enrichment in translation initiation factors, including eIF2α. Co-immunoprecipitation of tagged NUPR1 confirmed that the protein binds to both eIF2α and its phosphorylated form (p-eIF2α). Depletion of NUPR1 lead to prolonged phosphorylation of eIF2α. Finally, click chemistry revealed NUPR1-depleted Panc-1 cells displayed a decrease in the amount of nascent proteins in response to ER stress induction compared to wild-type cells. Thus, NUPR1 is necessary for an efficient PERK-branch activation by binding to the p-eIF2α and, consequently, promoting protein synthesis during the ER stress response.

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Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Cited by 77 publications

References 46 publications

Targeting intrinsically disordered proteins involved in cancer

Targeting intrinsically disordered proteins involved in cancer

Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1

The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2α

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Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Cited by 77 publications

References 46 publications

Targeting intrinsically disordered proteins involved in cancer

Targeting intrinsically disordered proteins involved in cancer

Targeting HIF-1&alpha; Function in Cancer through the Chaperone Action of NQO1

The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2α

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Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1