Targeting Protein Synthesis, Folding, and Degradation Pathways in Cancer

Pasqua, Adele E.; Wilding, Birgit; Cheeseman, Matthew D.; Jones, Keith

doi:10.1016/b978-0-12-409547-2.12395-9

Cited by 6 publications

(4 citation statements)

References 337 publications

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“…In this work, we studied the effect of the BETi OTX-015 on the metabolism of the D283 and D458 MYCdriven childhood MB cell lines. OTX-015 has been developed from the conventional BETi JQ1 to improve its pharmacokinetic profile and thus its potential in clinical use 16,17,22 .…”

Section: Discussionmentioning

confidence: 99%

Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition

Graziani

Garcia

Alcolado

et al. 2023

Sci Rep

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Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.

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Section: Discussionmentioning

confidence: 99%

Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition

Graziani

Garcia

Alcolado

et al. 2023

Sci Rep

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“…This reaction is unique to proteasomes, as they utilize the sidechain hydroxyl group of an NH 2 terminal threonine of the β5 subunit as the catalytic nucleophile. Furthermore, the N-terminal morpholine in carfilzomib increases its aqueous solubility to make it a potent drug for the treatment of MM ( 76 ) ( Figure 2 ). According Groll et al.…”

Section: Carfilzomib: a Promising Antineoplastic Drug Against R/rmmmentioning

confidence: 99%

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

et al. 2021

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The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

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“…It also serves to help maintain the shape of intracellular signaling proteins which are important to cancer cause, such as erbB2 [4], Bcr-Abl [5], and mutant p53 [6]. Moreover, there is a clear molecular dependence of cancer cells on functioning Hsp90 [7] which make Hsp90 become one of key cancer targets and there are many Hsp90 inhibitors designed [8].…”

Section: Introductionmentioning

confidence: 99%

Newly Designed Geldanamycin Analogues for Targeted Cancer-Causing Hsp90 Protein Inhibitor: Molecular Docking Study

Suttayasorranakhom

Jaramornburapong

Phuthawong

et al. 2022

KEM

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Cancer is currently a major public health concern worldwide. Previous studies have shown that heat shock protein 90 (Hsp90) is the key common cause of cancer. Thus, Hsp90 is one of the important molecular targets for the development of Hsp90 cancer drug based on geldanamycin (GDM) and alvespimycin (17-DMAG). Herein, novel geldanamycin derivatives, S1-S6 were designed as potential Hsp90 cancer drug by targeting signal transduction pathway, especially against oncogenic client protein from Hsp90. The binding of S1-S6 in the cavity of Hsp90 were investigated by molecular docking using the iGEMDOCK v2.1 software. The results illustrated that S1-S6 bound in the binding site of Hsp90 with similar manner to GDM and 17-DMAG. The binding energies of S1-S6 in Hsp90 (PDB ID:1YET) (-137.49 to -123.24 kcal/mol) were comparable to that of GDM (-133.06 kcal/mol) while the binding energies of S1-S6 in Hsp90 (PDB ID:1OSF) (-137.49 to -131.22 kcal/mol) were slightly higher than that of 17-DMAG (-145.31 kcal/mol). S1-S6 interacted well by hydrogen bonding with key amino acids in the binding site of Hsp90, which could inhibit the cancer cell growth. Therefore, S1-S6 containing novel geldanamycin derivatives could be promising molecules for anti-cancer drug against Hsp90 2 types in the future.

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Targeting Protein Synthesis, Folding, and Degradation Pathways in Cancer

Cited by 6 publications

References 337 publications

Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition

Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

Newly Designed Geldanamycin Analogues for Targeted Cancer-Causing Hsp90 Protein Inhibitor: Molecular Docking Study

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