| 1. |
- Azimi, Alireza, et al.
(author)
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Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
- 2018
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In: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 14:3
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Journal article (peer-reviewed)abstract
- Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression.
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| 2. |
- Danielsson, Jakob, et al.
(author)
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Total Synthesis of Dehaloperophoramidine : Evolution of a Synthesis
- 2017
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In: Strategies and Tactics in Organic Synthesis. - 1874-6004. ; 13, s. 217-242
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Book chapter (peer-reviewed)abstract
- This account describes our efforts toward developing a stereodivergent entry to perophoramidine and the communesin alkaloids. The original approach toward our simplified model substrates relied on a palladium-catalyzed carbopalladation–carbonylation of a tetrasubstituted olefin to install the vicinal all-carbon quaternary stereocenters present in the target molecules, the olefin's stereochemistry thus dictating the relative stereochemistry of the quaternary stereocenters. Although the carbonylation–carbopalladation sequence worked well for trisubstituted olefins, only premature esterification was observed when using tetrasubstituted alkene substrates. Our second approach made use of the latent symmetry embedded in our target molecules. A Diels–Alder reaction or SmI2-mediated bis-alkylation of isoindigo was to be used to access the communesin and perophoramidine scaffolds, respectively. We found that due to unfavorable thermodynamics, it was not possible to reach the communesin scaffold. However, two new complexity-generating, cascade reactions were encountered en route to the synthesis of dehaloperophoramidine, resulting in a short and efficient synthesis.
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| 3. |
- Langer, Krzysztof, et al.
(author)
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A conversational robotic lab assistant for automated microfluidic 3d microtissue production
- 2019
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In: 23rd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2019. - : Chemical and Biological Microsystems Society. ; , s. 888-889
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Conference paper (peer-reviewed)abstract
- The future of life science is linked to automation and microfluidics. Here we present a robotic lab assistant, a general automation platform for droplet microfluidics including a conversational mobile interface. We demonstrate the automated production of human cancer microtissues in droplets at a throughput of 85000 spheroids per microfluidic circuit per hour. The capability of automated spheroid generation is directly applicable to precision medicine and drug screening. Multiple cell lines were successfully tested, including cancer cell lines, co-cultures, and primary cells. The 3D-microtissues/spheroids were automatically assembled-incubated-retrieved with high viability for further drug screening analysis - the platform interfaces with standard labware.
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| 4. |
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| 5. |
- Mateus, André, 1986-, et al.
(author)
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Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
- 2017
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In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:30, s. E6231-E6239
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Journal article (peer-reviewed)abstract
- Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
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| 6. |
- Michel, Maurice, et al.
(author)
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Computational and Experimental Druggability Assessment of Human DNA Glycosylases
- 2019
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In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:7, s. 11642-11656
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Journal article (peer-reviewed)abstract
- Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.
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| 7. |
- Mou, Tian, et al.
(author)
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The transcriptome-wide landscape of molecular subtype-specific mRNA expression profiles in acute myeloid leukemia
- 2021
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In: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 96:5, s. 580-588
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Journal article (peer-reviewed)abstract
- Molecular classification of acute myeloid leukemia (AML) aids prognostic stratification and clinical management. Our aim in this study is to identify transcriptome-wide mRNAs that are specific to each of the molecular subtypes of AML. We analyzed RNA-sequencing data of 955 AML samples from three cohorts, including the BeatAML project, the Cancer Genome Atlas, and a cohort of Swedish patients to provide a comprehensive transcriptome-wide view of subtype-specific mRNA expression. We identified 729 subtype-specific mRNAs, discovered in the BeatAML project and validated in the other two cohorts. Using unique proteomics data, we also validated the presence of subtype-specific mRNAs at the protein level, yielding a rich collection of potential protein-based biomarkers for the AML community. To enable the exploration of subtype-specific mRNA expression by the broader scientific community, we provide an interactive resource to the public.
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| 8. |
- Pinheiro, Tiago, et al.
(author)
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A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth
- 2017
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In: Biochemical and Biophysical Research Communications - BBRC. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0006-291X .- 1090-2104. ; 494:3-4, s. 477-483
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is regarded as the most common malignant brain tumor but treatment options are limited. Thus, there is an unmet clinical need for compounds and corresponding targets that could inhibit GBM growth. We screened a library of 80 dopaminergic ligands with the aim of identifying compounds capable of inhibiting GBM cell line proliferation and survival. Out of 45 active compounds, 8 were further validated. We found that the dopamine receptor D2 antagonist trifluoperazine 2HC1 inhibits growth and proliferation of GBM cells in a dose dependent manner. Trifluoperazine's inhibition of GBM cells is cell line dependent and correlates with variations in dopamine receptor expression profile. We conclude that components of the dopamine receptor signaling pathways are potential targets for pharmacological interventions of GBM growth. (C) 2017 Elsevier Inc. All rights reserved.
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| 9. |
- Pinheiro, Tiago, et al.
(author)
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Reprint of : A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth
- 2018
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 499:2, s. 136-142
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is regarded as the most common malignant brain tumor but treatment options are limited. Thus, there is an unmet clinical need for compounds and corresponding targets that could inhibit GBM growth. We screened a library of 80 dopaminergic ligands with the aim of identifying compounds capable of inhibiting GBM cell line proliferation and survival. Out of 45 active compounds, 8 were further validated. We found that the dopamine receptor D2 antagonist trifluoperazine 2HCl inhibits growth and proliferation of GBM cells in a dose dependent manner. Trifluoperazine’s inhibition of GBM cells is cell line dependent and correlates with variations in dopamine receptor expression profile. We conclude that components of the dopamine receptor signaling pathways are potential targets for pharmacological interventions of GBM growth.
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| 10. |
- Reid, Steven E, et al.
(author)
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Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence
- 2024
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In: Oncogene. - 1476-5594.
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Journal article (peer-reviewed)abstract
- Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.
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