Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Ferguson, Ian; Lin, Yu-Hsiu T.; Lam, Christine; Shao, Hao; Tharp, Kevin M.; Hale, Martina; Kasap, Corynn; Mariano, Margarette C.; Kishishita, Audrey; Escobar, Bonell Patiño; Mandal, Kunal Kumar; Steri, Veronica; Wang, Donghui; Phojanakong, Paul; Tuomivaara, Sami T.; Hann, Byron; Ness, Brian Van; Gestwicki, Jason E.; Wiita, Arun P.

doi:10.1016/j.chembiol.2022.06.010

Cited by 16 publications

(8 citation statements)

References 83 publications

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“…We determined the expression of 254 highly frequently mutated genes in various subpopulations of plasma cells. The results showed the expression of tumor malignant characteristic genes such as CDKN2A CKS1B, HSPA9, IDH2 and MYC among different subpopulations of plasma cells [33][34][35][36][37], with high expression in plasma cell_2 (Figure S4). Importantly, we detected heterogeneity in multiple components of proteasomes and PABPC1 ,witch is involved in alternative polyadenylation, among the different subpopulations of plasma cells.This is consistent with what has been reported [38,39].…”

Section: The Heterogeneity Of Plasma Cells In MMmentioning

confidence: 99%

Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets

Liu,

Wang,

Peng

et al. 2024

Preprint

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Multiple myeloma (MM) is a heterogeneous and incurable tumor characterized by the malignant proliferation of plasma cells. It is necessary to clarify the heterogeneity of MM and identify new theranostic targets. We constructed a single-cell transcriptome profile of 48 293 bone marrow cells from MM patients and health donors (HDs) annotated with 7 continuous B lymphocyte lineages. Through CellChat, we discovered that the communication among B lymphocyte lineages between MM and HDs was disrupted, and unique signaling molecules were observed. Through pseudotime analysis, it was found that the differences between MM and HDs were mainly reflected in plasma cells. These differences are primarily related to various biological processes involving mitochondria. Then, we identified the key subpopulation associated with malignant proliferation of plasma cells. This group of cells exhibited strong proliferation ability, high CNV scores, high expression of frequently mutated genes, and strong glucose metabolic activity. Furthermore, we demonstrated the therapeutic potential of WNK1 as a target. Our study provides new insights into the development of B cells and the heterogeneity of plasma cells in MM, and suggests that WNK1 is a potential therapeutic target for MM.

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Section: The Heterogeneity Of Plasma Cells In MMmentioning

confidence: 99%

Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets

Liu,

Wang,

Peng

et al. 2024

Preprint

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“…Allosteric HSP70 inhibitors, named JG compounds, have also been explored as myeloma therapeutics. They impact myeloma proteostasis by destabilizing the 55S mitoribosome thus suggesting JGs have the most prominent anti-myeloma effect through mitochondrial-localized HSP70 (i.e., GRP75) rather than through the inhibition of cytosolic HSP70 [ 125 ]. A very recent work identifies HSP70 family members as the “managers” of the molecular network of the proteasome machinery, except for controlling Nrf1/2.…”

Section: Hsp70 and Its Targeting In Onco-hematological Diseasesmentioning

confidence: 99%

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

et al. 2023

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The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

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“…Cationic Hsp70 inhibitors such as compound 3b ( Figure 4 , JG-98) were identified as mortalin inhibitors with pronounced activity against proteasome inhibitor-resistant MM cells associated with 55S mitoribosome degradation [ 90 ]. Compound 3c ( Figure 4 , MKT-077) overlaps with the p53-binding region of mortalin, releasing active p53 followed by upregulation of p21 in treated cancer cells [ 91 , 92 ].…”

Section: Hsp70 Inhibitorsmentioning

confidence: 99%

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

Nitzsche

Höpfner

Biersack

2023

IJMS

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A class of chaperones dubbed heat shock protein 70 (Hsp70) possesses high relevance in cancer diseases due to its cooperative activity with the well-established anticancer target Hsp90. However, Hsp70 is closely connected with a smaller heat shock protein, Hsp40, forming a formidable Hsp70-Hsp40 axis in various cancers, which serves as a suitable target for anticancer drug design. This review summarizes the current state and the recent developments in the field of (semi-)synthetic small molecule inhibitors directed against Hsp70 and Hsp40. The medicinal chemistry and anticancer potential of pertinent inhibitors are discussed. Since Hsp90 inhibitors have entered clinical trials but have exhibited severe adverse effects and drug resistance formation, potent Hsp70 and Hsp40 inhibitors may play a significant role in overcoming the drawbacks of Hsp90 inhibitors and other approved anticancer drugs.

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Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

Cited by 16 publications

References 83 publications

Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets

Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

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