Dienone Compounds: Targets and Pharmacological Responses

Bazzaro, Martina; Linder, Stig

doi:10.1021/acs.jmedchem.0c00812

Cited by 16 publications

(33 citation statements)

References 156 publications

(560 reference statements)

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“…Previous reports described a similar sensitivity of TP53 ‐wild type and TP53‐ mutant cell lines to b‐AP15. Bazzaro et al indicated that IC 50 of TP53 ‐wild type cell lines in the NCI 60 panel to b‐AP15 is 0.18 μmol/L, and IC 50 of TP53‐ mutant cell lines is 0.15 μmol/L ( P = .70) 49 . Didier et al reported that b‐AP15 has an antitumor effect irrespective of mutation status on BRAF , NRAS , and TP53 9 .…”

Section: Discussionmentioning

confidence: 99%

“…Bazzaro et al indicated that IC 50 of TP53 ‐wild type cell lines in the NCI 60 panel to b‐AP15 is 0.18 μmol/L, and IC 50 of TP53‐ mutant cell lines is 0.15 μmol/L ( P = .70). 49 Didier et al reported that b‐AP15 has an antitumor effect irrespective of mutation status on BRAF , NRAS , and TP53 . 9 D'Arcy et al reported using isogenic clones of HCT‐116 that b‐AP15 induced apoptosis that was insensitive to overexpression of Bcl‐2 and disruption of TP53.…”

Section: Discussionmentioning

confidence: 99%

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VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

et al. 2021

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A novel proteasome deubiquitinase inhibitor, VLX1570, has been highlighted as a promising therapeutic agent mainly for lymphoid neoplasms and solid tumors. We examined in vitro effects of VLX1570 on eight myeloid and three lymphoid leukemia cell lines. From cell culture studies, 10 out of 11 cell lines except K562 were found to be susceptible to VLX1570 treatment and it inhibited cell growth mainly by apoptosis. Next, to identify the signaling pathways associated with apoptosis, we performed gene expression profiling using HL‐60 with or without 50 nmol/L of VLX1570 for 3 hours and demonstrated that VLX1570 induced the genetic pathway involved in “heat shock transcription factor 1 (HSF1) activation”, “HSF1 dependent transactivation”, and “Regulation of HSF1 mediated heat shock response”. VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitin proteasome system, the expression of heme oxygenase‐1, and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP, and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP‐1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti‐leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

et al. 2021

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“…RA413S and RA414 also both show stronger binding to their 42kDa protein target, previously identified as RPN13, in ovarian cancer cell lysates than RA183. Although these reactive compounds have potential for off-target effects [50], RA190 and related inhibitors bind to cysteine 88 within a groove of RPN13 that mediates binding to the proteasome via RPN2 [16,17]. This suggests that drug blockade of RPN13 association to the 19S RP inhibits both proteasomal degradation and deubiquitinase activity of its binding partner UCH37.…”

Section: Discussionmentioning

confidence: 99%

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

et al. 2021

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Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome’s 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

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“…So manual test is feasible, but for a limited number of samples. We took ten articles [28][29][30][31][32][33][34][35][36][37] to test our method on the real data. Structures that represent reaction mechanisms were excluded, so we regarded only molecules and Markush templates.…”

Section: Validation On Real Datamentioning

confidence: 99%

Image2SMILES: Transformer-based Molecular Optical Recognition Engine

Khokhlov¹,

Krasnov²,

Fedorov³

et al. 2021

Preprint

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The rise of deep learning in various scientific and technology areas promotes the development of AI-based tools for information retrieval. Optical recognition of organic structures is a key part of the automated extraction of chemical information. However, this is a challenging task because there is a large variety of representation styles. In this research, we present a Transformer-based artificial neural network to convert images of organic structures to molecular structures. To train the model, we created a comprehensive data generator that stochastically simulates various drawing styles, functional groups, functional group placeholders (R-groups), and visual contamination. We demonstrate that the Transformer-based architecture can gather chemical insights from our generator with almost absolute confidence. That means that, with Transformer, one can fully concentrate on data simulation to build a good recognition model. A web demo of our optical recognition engine is available online at <i>Syntelly</i> platform.

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Dienone Compounds: Targets and Pharmacological Responses

Cited by 16 publications

References 156 publications

VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

Image2SMILES: Transformer-based Molecular Optical Recognition Engine

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