Research Repository

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1-Hydroxy-xanthine derivatives inhibit the human Caf1 nuclease and Caf1-containing nuclease complexes via Mg2+-dependent binding (2019)
Journal Article
Airhihen, B., Pavanello, L., Jadhav, G. P., Fischer, P. M., & Winkler, G. S. (2019). 1-Hydroxy-xanthine derivatives inhibit the human Caf1 nuclease and Caf1-containing nuclease complexes via Mg2+-dependent binding. FEBS Open Bio, doi:10.1002/2211-5463.12605

In eukaryotic cells, cytoplasmic mRNA is characterised by a 3’ poly(A) tail. The shortening and removal of poly(A) tails (deadenylation) by the Ccr4‐Not nuclease complex leads to reduced translational efficiency and RNA degradation. Using recombinant... Read More

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system (2018)
Journal Article
Lee, J. B., Zgair, A., Malec, J., Kim, T. H., Kim, M. G., Ali, J., …Gershkovich, P. (2018). Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system. Journal of Controlled Release, 286, (10-19). doi:10.1016/j.jconrel.2018.07.022. ISSN 0168-3659

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for... Read More

Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B (2018)
Journal Article
Zyryanova, A. F., Weis, F., Faille, A., Abo Alard, A., Crespillo-Casado, A., Sekine, Y., …Ron, D. (2018). Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359(6383), doi:10.1126/science.aar5129. ISSN 0036-8075

The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) tha... Read More

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor (2018)
Journal Article
Whittaker, S. R., Barlow, C., Martin, M. P., Mancusi, C., Wagner, S., Self, A., …Workman, P. (in press). Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular Oncology, 12(3), doi:10.1002/1878-0261.12148. ISSN 1574-7891

Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecul... Read More

Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs (2017)
Journal Article
Fischer, P. M. (in press). Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs. Journal of Medicinal Chemistry, 61(9), doi:10.1021/acs.jmedchem.7b00772. ISSN 0022-2623

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose–response variability and the risks of bleeding. The approval of fond... Read More

Development of cordycepin formulations for preclinical and clinical studies (2017)
Journal Article
Lee, J. B., Adrower, C., Qin, C., Fischer, P. M., Moor, C. H. D., & Gershkovich, P. (in press). Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech, doi:10.1208/s12249-017-0795-0. ISSN 1530-9932

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is... Read More

PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz (2017)
Journal Article
Crespillo-Casado, A., Chambers, J. E., Fischer, P. M., Marciniak, S. J., & Ron, D. (2017). PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLife, 6, doi:10.7554/eLife.26109. ISSN 2050-084X

Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylid... Read More

Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease (2017)
Journal Article
Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., …Fischer, P. M. (2017). Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31(7), doi:10.1096/fj.201601305R. ISSN 0892-6638

β-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-th... Read More

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays (2017)
Journal Article
Lee, J. B., Zgair, A., Taha, D. A., Zang, X., Kagan, L., Kim, T. H., …Gershkovich, P. (2017). Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays. European Journal of Pharmaceutics and Biopharmaceutics, 114, doi:10.1016/j.ejpb.2016.12.027. ISSN 0939-6411

In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The... Read More

Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma (2016)
Journal Article
Lee, J. B., Zgair, A., Kim, T. H., Kim, M. G., Yoo, S. D., Fischer, P. M., & Gershkovich, P. (2017). Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma. Journal of Chromatography B, 1040, doi:10.1016/j.jchromb.2016.11.024. ISSN 1570-0232

Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple... Read More

Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview (2016)
Journal Article
Fischer, P. M. (2017). Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview. Medicinal Research Reviews, 37(2), doi:10.1002/med.21409. ISSN 0198-6325

Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs ha... Read More

GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors (2016)
Journal Article
Emtage, A. L., Mistry, S. N., Fischer, P. M., Kellam, B., & Laughton, C. A. (2016). GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors. Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2016.1226197. ISSN 0739-1102

G protein-coupled receptors (GPCRs) are proteins of pharmaceutical importance, with over 30% of all drugs in clinical use targeting them. Increasing numbers of X-ray crystal (XRC) structures of GPCRs offer a wealth of data relating to ligand binding.... Read More