Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma

Kyani, Anahita; Tamura, Shuzo; Yang, Suhui; Shergalis, Andrea; Samanta, Soma; Kuang, Yuting; Ljungman, Mats; Neamati, Nouri

doi:10.1002/cmdc.201700629

Cited by 63 publications

(68 citation statements)

References 66 publications

(112 reference statements)

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“…PACMA31 has been demonstrated by our lab in this report and others to be non-specific towards PDI (PDIA1), and can inhibit other PDI family members, such as ERp57 22. Furthermore, we identified a potent PDI inhibitor, 35G8 , that was toxic in a 2D cancer model 28. However, 35G8 , as a known redox-cycling molecule, does not possess drug-like properties.…”

Section: Introductionmentioning

confidence: 70%

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Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes

Xu¹,

Liu²,

Yang³

et al. 2019

Theranostics

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Aberrant overexpression of endoplasmic reticulum (ER)-resident oxidoreductase protein disulfide isomerase (PDI) plays an important role in cancer progression. In this study, we demonstrate that PDI promotes glioblastoma (GBM) cell growth and describe a class of allosteric PDI inhibitors that are selective for PDI over other PDI family members. Methods : We performed a phenotypic screening triage campaign of over 20,000 diverse compounds to identify PDI inhibitors cytotoxic to cancer cells. From this screen, BAP2 emerged as a lead compound, and we assessed BAP2 -PDI interactions with gel filtration, thiol-competition assays, and site-directed mutagenesis studies. To assess selectivity, we compared BAP2 activity across several PDI family members in the PDI reductase assay. Finally, we performed in vivo studies with a mouse xenograft model of GBM combining BAP2 and the standard of care (temozolomide and radiation), and identified affected gene pathways with nascent RNA sequencing (Bru-seq). Results : BAP2 and related analogs are novel PDI inhibitors that selectively inhibit PDIA1 and PDIp. Though BAP2 contains a weak Michael acceptor, interaction with PDI relies on Histidine 256 in the b' domain of PDI, suggesting allosteric binding. Furthermore, both in vitro and in vivo , BAP2 reduces cell and tumor growth. BAP2 alters the transcription of genes involved in the unfolded protein response, ER stress, apoptosis and DNA repair response. Conclusion : These results indicate that BAP2 has anti-tumor activity and the suppressive effect on DNA repair gene expression warrants combination with DNA damaging agents to treat GBM.

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Section: Introductionmentioning

confidence: 70%

“…Chalcone-containing compounds inhibit PDI. We performed a two-step screening of a subset of our in-house drug-like small molecule libraries (Figure 2A) 28. From an initial screen for cytotoxicity, 443 compounds with high potency were identified and tested for PDI inhibition.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes

Xu¹,

Liu²,

Yang³

et al. 2019

Theranostics

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confidence: 99%

Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

Beatty

Singh

Tyurina

et al. 2019

Preprint

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Recent studies have shown that cancer cells, including renal cell carcinoma, melanoma and glioblastoma are vulnerable to ferroptosis [10][11][12][13][14][15][16] . Furthermore therapy-resistant mesenchymal cancer cells exhibit a greater reliance on GPX4 activity for survival 10,17 . These findings have highlighted the therapeutic potential of pro-ferroptotic agents, but it remains unclear whether induction of ferroptosis can be used therapeutically to selectively kill cancer cells in vivo 1 . A major challenge to testing this hypothesis has been the absence of selective ferroptosis-inducing agents, such as GPX4 inhibitors, suitable for use in vivo 18 .While suppressing the GPX4-mediated antioxidant response is one approach to induce ferroptosis, a complementary approach is to promote the production of lipid hydroperoxides by increasing the availability of their PUFA precursors. Hydroperoxides can spread by a free radical-mediated chain reaction leading to oxidation of adjacent PUFAs, and consequently higher PUFA levels could increase vulnerability to the propagation of lipid peroxides. Indeed, supplementation of cells with the PUFA arachidonic acid sensitizes them to ferroptosis triggered by GPX4 inhibitors 19 . Importantly, this approach to enhancing ferroptosis would exploit the propensity of cancer cells to scavenge fatty acids from their environment 20 .Here we report a vulnerability in triple-negative breast cancer (TNBC) to ferroptosis associated with the accumulation of PUFAs, and identified conjugated linolenic fatty acids as PUFAs that induce ferroptosis.Mechanistically, accumulation of PUFAs in TNBC triggered ferroptosis by a mode of action distinct from canonical ferroptosis inducers. We show that oral administration of tung nut oil, naturally rich in the conjugated PUFA α-eleostearate, has anti-cancer activity in a xenograft model of TNBC. α-Eleostearate metabolites could be detected in tumors of treated mice and was associated with expression of ferroptotic markers. These results introduce a distinct class of ferroptosis inducers and offer novel insights into the molecular basis of ferroptotic sensitivity. The tractability of these dietary, pro-ferroptotic fatty acids addresses the current lack of effective GPX4 inhibitors for use in vivo and suggests a novel opportunity to exploit a metabolic liability in an aggressive breast cancer subtype.

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“…In a medium-throughput screen of 20,000 drug-like compounds derived from a diverse library, QCBT7 was one of the most cytotoxic hits and had an IC 50 value of 0.6 μM in HCT 116 cells [20]. QCBT7 was further tested in the pancreatic cancer cell lines, showing IC 50 values of 2.6 μM and 1.1 μM in MIA PaCa-2 and PANC-1 cells, respectively (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and mechanistic studies of quinolin-chlorobenzothioate derivatives with proteasome inhibitory activity in pancreatic cancer cell lines

Zhou

Jin

Liu

et al. 2018

European Journal of Medicinal Chemistry

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Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response.

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Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma

Cited by 63 publications

References 66 publications

Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes

Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes

Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

Synthesis and mechanistic studies of quinolin-chlorobenzothioate derivatives with proteasome inhibitory activity in pancreatic cancer cell lines

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