Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4.

Nature. 2017 Dec 06;:

Authors: Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, Ozdian T, Bartkova J, Turi Z, Moudry P, Kraus M, Michalova M, Vaclavkova J, Dzubak P, Vrobel I, Pouckova P, Sedlacek J, Miklovicova A, Kutt A, Li J, Mattova J, Driessen C, Dou QP, Olsen J, Hajduch M, Cvek B, Deshaies RJ, Bartek J

Abstract
Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

PMID: 29211715 [PubMed - as supplied by publisher]

Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome.

J Alzheimers Dis. 2018;61(1):53-65

Authors: Chatterjee P, Roy D, Rathi N

Abstract
BACKGROUND: Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD.
OBJECTIVE: In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome.
METHODS: Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied.
RESULTS: The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs.
CONCLUSIONS: The findings of our work might provide insight into future AD epigenetic-therapeutics.

PMID: 29199645 [PubMed - in process]

[Drug Repositioning Research Utilizing a Large-scale Medical Claims Database to Improve Survival Rates after Cardiopulmonary Arrest].

Yakugaku Zasshi. 2017;137(12):1439-1442

Authors: Zamami Y, Niimura T, Takechi K, Imanishi M, Koyama T, Ishizawa K

Abstract
 Approximately 100000 people suffer cardiopulmonary arrest in Japan every year, and the aging of society means that this number is expected to increase. Worldwide, approximately 100 million develop cardiac arrest annually, making it an international issue. Although survival has improved thanks to advances in cardiopulmonary resuscitation, there is a high rate of postresuscitation encephalopathy after the return of spontaneous circulation, and the proportion of patients who can return to normal life is extremely low. Treatment for postresuscitation encephalopathy is long term, and if sequelae persist then nursing care is required, causing immeasurable economic burdens as a result of ballooning medical costs. As at present there is no drug treatment to improve postresuscitation encephalopathy as a complication of cardiopulmonary arrest, the development of novel drug treatments is desirable. In recent years, new efficacy for existing drugs used in the clinical setting has been discovered, and drug repositioning has been proposed as a strategy for developing those drugs as therapeutic agents for different diseases. This review describes a large-scale database study carried out following a discovery strategy for drug repositioning with the objective of improving survival rates after cardiopulmonary arrest and discusses future repositioning prospects.

PMID: 29199254 [PubMed - in process]

Disulfiram as a novel inactivator of Giardia lamblia triosephosphate isomerase with antigiardial potential.

Int J Parasitol Drugs Drug Resist. 2017 Nov 30;7(3):425-432

Authors: Castillo-Villanueva A, Rufino-González Y, Méndez ST, Torres-Arroyo A, Ponce-Macotela M, Martínez-Gordillo MN, Reyes-Vivas H, Oria-Hernández J

Abstract
Giardiasis, the infestation of the intestinal tract by Giardia lamblia, is one of the most prevalent parasitosis worldwide. Even though effective therapies exist for it, the problems associated with its use indicate that new therapeutic options are needed. It has been shown that disulfiram eradicates trophozoites in vitro and is effective in vivo in a murine model of giardiasis; disulfiram inactivation of carbamate kinase by chemical modification of an active site cysteine has been proposed as the drug mechanism of action. The triosephosphate isomerase from G. lamblia (GlTIM) has been proposed as a plausible target for the development of novel antigiardial pharmacotherapies, and chemical modification of its cysteine 222 (C222) by thiol-reactive compounds is evidenced to inactivate the enzyme. Since disulfiram is a cysteine modifying agent and GlTIM can be inactivated by modification of C222, in this work we tested the effect of disulfiram over the recombinant and trophozoite-endogenous GlTIM. The results show that disulfiram inactivates GlTIM by modification of its C222. The inactivation is species-specific since disulfiram does not affect the human homologue enzyme. Disulfiram inactivation induces only minor conformational changes in the enzyme, but substantially decreases its stability. Recombinant and endogenous GlTIM inactivates similarly, indicating that the recombinant protein resembles the natural enzyme. Disulfiram induces loss of trophozoites viability and inactivation of intracellular GlTIM at similar rates, suggesting that both processes may be related. It is plausible that the giardicidal effect of disulfiram involves the inactivation of more than a single enzyme, thus increasing its potential for repurposing it as an antigiardial drug.

PMID: 29197728 [PubMed - as supplied by publisher]

When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data.

Assay Drug Dev Technol. 2017 Dec 01;:

Authors: Pulley JM, Jerome RN, Zaleski NM, Shirey-Rice JK, Pruijssers AJ, Lavieri RR, Chettiar SN, Naylor HM, Aronoff DM, Edwards DA, Niswender CM, Dugan LL, Crofford LJ, Bernard GR, Holroyd KJ

Abstract
Many animal models of disease are suboptimal in their representation of human diseases and lack of predictive power in the success of pivotal human trials. In the context of repurposing drugs with known human safety, it is sometimes appropriate to conduct the "last experiment first," that is, progressing directly to human investigations. However, there are not accepted criteria for when to proceed straight to humans to test a new indication. We propose a specific set of criteria to guide the decision-making around when to initiate human proof of principle without preclinical efficacy studies in animal models. This approach could accelerate the transition of novel therapeutic approaches to human applications.

PMID: 29193979 [PubMed - as supplied by publisher]

MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia.

EBioMedicine. 2017 Nov 22;:

Authors: Xu D, Ham AG, Tivis RD, Caylor ML, Tao A, Flynn ST, Economen PJ, Dang HK, Johnson RW, Culbertson VL

Abstract
In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.

PMID: 29191560 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2017/12/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2017/11/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2017/11/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Mechanism informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis.

Mol Cancer Ther. 2017 Nov 22;:

Authors: Huang HC, Liu J, Baglo Y, Rizvi I, Anbil S, Pigula M, Hasan T

Abstract
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations.

PMID: 29167313 [PubMed - as supplied by publisher]

iPSC-Based Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β Combination for Alzheimer's Disease.

Cell Rep. 2017 Nov 21;21(8):2304-2312

Authors: Kondo T, Imamura K, Funayama M, Tsukita K, Miyake M, Ohta A, Woltjen K, Nakagawa M, Asada T, Arai T, Kawakatsu S, Izumi Y, Kaji R, Iwata N, Inoue H

Abstract
In the process of drug development, in vitro studies do not always adequately predict human-specific drug responsiveness in clinical trials. Here, we applied the advantage of human iPSC-derived neurons, which offer human-specific drug responsiveness, to screen and evaluate therapeutic candidates for Alzheimer's disease (AD). Using AD patient neurons with nearly 100% purity from iPSCs, we established a robust and reproducible assay for amyloid β peptide (Aβ), a pathogenic molecule in AD, and screened a pharmaceutical compound library. We acquired 27 Aβ-lowering screen hits, prioritized hits by chemical structure-based clustering, and selected 6 leading compounds. Next, to maximize the anti-Aβ effect, we selected a synergistic combination of bromocriptine, cromolyn, and topiramate as an anti-Aβ cocktail. Finally, using neurons from familial and sporadic AD patients, we found that the cocktail showed a significant and potent anti-Aβ effect on patient cells. This human iPSC-based platform promises to be useful for AD drug development.

PMID: 29166618 [PubMed - in process]

Identifying Candidates for Breast Cancer Using Interactions of Chemicals and Proteins.

Comb Chem High Throughput Screen. 2017 Nov 20;:

Authors: Lu J, Shang K, Bi Y

Abstract
Breast cancer is one of the major cause of cancer death in women worldwide. Therefore, it is urgent to discovery novel drugs or design effective treatments for this disease. However, the research and development of drugs by using only experimental methods is always time-consuming and expensive. With the development of computer science, some advanced computational methods can make full use of known knowledge to design candidate drugs, thereby reducing the cost and time of experimental testing. In this study, a computational method was proposed to identify novel candidates for breast cancer. The approved drugs and genes of breast cancer were taken as the input of the method. The chemical-chemical interactions and chemical-protein interactions were adopted to extract possible candidates from large numbers of existing chemicals. The method included three stages, termed searching stage, filtering stage and selecting stage. In the searching stage, chemicals that have associations with approved drugs were extracted. Then, these chemicals were screened in the filtering stage to discard those that have no relationships with breast cancer related genes. Finally, a clustering algorithm, termed as EM clustering algorithm, was employed to identify the potential candidates in the selecting stage. An extensive analysis by retrieving literature indicated that multiple selected candidates, such as gefitinib, canertinib and sirolimus, that have been approved for other diseases were confirmed to have anti-breast cancer activities. Therefore, this method can provide some valuable instructions for drug repositioning.

PMID: 29165068 [PubMed - as supplied by publisher]

Comparison of Quantitative Mass Spectrometry Platforms for Monitoring Kinase ATP Probe Uptake in Lung Cancer.

J Proteome Res. 2017 Nov 22;:

Authors: Hoffman MA, Fang B, Haura EB, Rix U, Koomen JM

Abstract
Recent developments in instrumentation and bioinformatics have led to new quantitative mass spectrometry platforms including LC-MS/MS with data-independent acquisition (DIA) and targeted analysis using parallel reaction monitoring mass spectrometry (LC-PRM), which provide alternatives to well-established methods, such as LC-MS/MS with data-dependent acquisition (DDA) and targeted analysis using multiple reaction monitoring mass spectrometry (LC-MRM). These tools have been used to identify signaling perturbations in lung cancers and other malignancies, supporting the development of effective kinase inhibitors and, more recently, providing insights into therapeutic resistance mechanisms and drug repurposing opportunities. However, detection of kinases in biological matrices can be challenging; therefore, activity-based protein profiling enrichment of ATP-utilizing proteins was selected as a test case for exploring the limits of detection of low-abundance analytes in complex biological samples. To examine the impact of different MS acquisition platforms, quantification of kinase ATP uptake following kinase inhibitor treatment was analyzed by four different methods: LC-MS/MS with DDA and DIA, LC-MRM, and LC-PRM. For discovery data sets, DIA increased the number of identified kinases by 21% and reduced missingness when compared with DDA. In this context, MRM and PRM were most effective at identifying global kinome responses to inhibitor treatment, highlighting the value of a priori target identification and manual evaluation of quantitative proteomics data sets. We compare results for a selected set of desthiobiotinylated peptides from PRM, MRM, and DIA and identify considerations for selecting a quantification method and postprocessing steps that should be used for each data acquisition strategy.

PMID: 29164889 [PubMed - as supplied by publisher]

Sustained Complete Response to Metronomic Chemotherapy in a Child with Refractory Atypical Teratoid Rhabdoid Tumor: A Case Report.

Front Pharmacol. 2017;8:792

Authors: Berland M, Padovani L, Rome A, Pech-Gourg G, Figarella-Branger D, André N

Abstract
Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive embryonal tumor of the central nervous system with a dismal prognosis and no definitive guidelines for treatment, especially at relapse or in case of refractory disease. Metronomic chemotherapy (MC) has emerged as a new treatment option in solid malignancies, with lower toxicity and is frequently combined with drug repositioning. We report a case of ATRT in an 8-year-old boy who progressed during multimodal therapy including surgical resection, chemotherapy and radiotherapy. He was treated with MC involving continuous oral celecoxib with alternating metronomic etoposide and cyclophosphamide, in combination with biweekly bevacizumab and monthly intrathecal liposomal cytarabine. To date, he remains clinically and symptomatically disease-free with a follow-up of 10 months. The treatment was well-tolerated. Metronomics represent a possible alternative regimen for children with recurrent or progressive ATRT.

PMID: 29163174 [PubMed]

SUMOylation in brain ischemia: Patterns, targets, and translational implications.

J Cereb Blood Flow Metab. 2017 Jan 01;:271678X17742260

Authors: Bernstock JD, Yang W, Ye DG, Shen Y, Pluchino S, Lee YJ, Hallenbeck JM, Paschen W

Abstract
Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia.

PMID: 29148315 [PubMed - as supplied by publisher]

Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO conjugation via the inhibition of SUMO-specific protease (SENP)2.

FASEB J. 2017 Nov 16;:

Authors: Bernstock JD, Ye D, Smith JA, Lee YJ, Gessler FA, Yasgar A, Kouznetsova J, Jadhav A, Wang Z, Pluchino S, Zheng W, Simeonov A, Hallenbeck JM, Yang W

Abstract
The development of novel neuroprotective treatments for acute stroke has been fraught with failures, which supports the view of ischemic brain damage as a highly complex multifactorial process. Post-translational modifications such as small ubiquitin-like modifier (SUMO)ylation have emerged as critical molecular regulatory mechanisms in states of both homeostasis and ischemic stress, as evidenced by our previous work. Accordingly, the clinical significance of the selective control of the global SUMOylation process has become apparent in studies of ischemic pathobiology and pathophysiology. Herein, we describe a process capable of identifying and characterizing small molecules with the potential of targeting the SUMO system through inhibition of SUMO deconjugation in an effort to develop novel stroke therapies.-Bernstock, J. D., Ye, D., Smith, J. A., Lee, Y.-J., Gessler, F. A., Yasgar, A., Kouznetsova, J., Jadhav, A., Wang, Z., Pluchino, S., Zheng, W., Simeonov, A., Hallenbeck, J. M., Yang, W. Quantitative high-throughput screening identifies cytoprotective molecules that enhance SUMO-conjugation via the inhibition of SUMO-specific protease (SENP)2.

PMID: 29146736 [PubMed - as supplied by publisher]

Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells.

J Control Release. 2017 Nov 13;:

Authors: Joris F, De Backer L, Van de Vyver T, Bastiancich C, De Smedt SC, Raemdonck K

Abstract
Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.

PMID: 29146245 [PubMed - as supplied by publisher]

The Immunomodulatory Drug Glatiramer Acetate is Also an Effective Antimicrobial Agent that Kills Gram-negative Bacteria.

Sci Rep. 2017 Nov 15;7(1):15653

Authors: Christiansen SH, Murphy RA, Juul-Madsen K, Fredborg M, Hvam ML, Axelgaard E, Skovdal SM, Meyer RL, Sørensen UBS, Möller A, Nyengaard JR, Nørskov-Lauritsen N, Wang M, Gadjeva M, Howard KA, Davies JC, Petersen E, Vorup-Jensen T

Abstract
Classic drug development strategies have failed to meet the urgent clinical needs in treating infections with Gram-negative bacteria. Repurposing drugs can lead to timely availability of new antibiotics, accelerated by existing safety profiles. Glatiramer acetate (GA) is a widely used and safe formulation for treatment of multiple sclerosis. It contains a large diversity of essentially isomeric polypeptides with the cationic and amphiphilic character of many antimicrobial peptides (AMP). Here, we report that GA is antibacterial, targeting Gram-negative organisms with higher activity towards Pseudomonas aeruginosa than the naturally-occurring AMP LL-37 in human plasma. As judged from flow cytometric assays, bacterial killing by GA occurred within minutes. Laboratory strains of Escherichia coli and P. aeruginosa were killed by a process of condensing intracellular contents. Efficient killing by GA was also demonstrated in Acinetobacter baumannii clinical isolates and approximately 50% of clinical isolates of P. aeruginosa from chronic airway infection in CF patients. By contrast, the Gram-positive Staphylococcus aureus cells appeared to be protected from GA by an increased formation of nm-scale particulates. Our data identify GA as an attractive drug repurposing candidate to treat infections with Gram-negative bacteria.

PMID: 29142299 [PubMed - in process]

Competitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits GSK3β and Activates WNT Signaling.

Mol Cancer Res. 2017 Nov 13;:

Authors: Cousins EM, Goldfarb D, Yan F, Roques J, Darr DB, Johnson GL, Major MB

Abstract
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response MIB/MS profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3α and β) and Ca2+/calmodulin-dependent protein kinase II delta and gamma (CAMK2δ and γ) as the most potently inhibited. Cell-based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits GSK3α/β and CAMK2γ/δ kinase activity at low nanomolar concentrations. GSK3β phosphorylates β-catenin to suppress WNT signaling, while abemaciclib (but not palbociclib or ribociclib) potently activates β-catenin-dependent WNT signaling. These data illustrate the power of competitive chemical proteomics to define kinase target specificities for kinase inhibitors, thus informing clinical efficacy, dose-limiting toxicities, and drug-repurposing efforts. This study uses a rapid and quantitative proteomics approach to define inhibitor-target data for commonly administered therapeutics and provides a cell-based alternative to in vitro kinome profiling.

PMID: 29133594 [PubMed - as supplied by publisher]

Drug repositioning meets precision in glioblastoma.

Clin Cancer Res. 2017 Nov 13;:

Authors: Wick W, Kessler T

Abstract
Glioblastoma has a gigantic unmet medical need. Molecular knowledge has evolved substantially, including data on clonal selection with progression. Past trials for all-comers may have produced false negative results. Molecular precision at progression needs workup of new tissue and revisiting drugs with focus on brain tumor penetration may yield surprises.

PMID: 29133572 [PubMed - as supplied by publisher]