Article
Medicine, Research & Experimental
Michael D. Kim, Charles D. Bengtson, Makoto Yoshida, Asef J. Niloy, John S. Dennis, Nathalie Baumlin, Matthias Salathe
Summary: Highly effective modulator therapies greatly improve prognosis for cystic fibrosis patients. However, not all patients with the most common F508del mutation in CFTR benefit from ETI therapy. The study found that elevated levels of active TGF-??1 in the upper airway were associated with poor response to ETI, as evidenced by low sweat chloride concentrations and lack of lung function improvements. TGF-??1 impaired the function of corrected F508del-CFTR and led to increased absorption rates of airway surface liquid and mucus hyperconcentration in vitro. Losartan reversed the negative effects of TGF-??1 and improved ASL hydration in CF airway epithelium.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Review
Biochemistry & Molecular Biology
Evelina Moliteo, Monica Sciacca, Antonino Palmeri, Maria Papale, Sara Manti, Giuseppe Fabio Parisi, Salvatore Leonardi
Summary: There is substantial evidence that patients with cystic fibrosis (CF) have higher oxidative stress levels, which contribute to the progression of chronic lung damage. CF patients exhibit an abnormal proinflammatory environment in their airways even before infection, possibly due to elevated oxidative stress and abnormal lipid metabolism. CFTR deficiency appears to cause a redox imbalance in epithelial cells and extracellular fluids.
Article
Pediatrics
Qiyu Li, Siyuan Liu, Xuemei Ma, Jiaping Yu
Summary: This meta-analysis evaluated the effectiveness and safety of small molecule therapy in children diagnosed with cystic fibrosis (CF). The results showed that CFTR modulators can improve respiratory function, lung clearance index, sweat chloride concentration, and other aspects of function in children with CF, with comparable adverse events compared to the placebo group.
FRONTIERS IN PEDIATRICS
(2022)
Review
Pharmacology & Pharmacy
Yizi Wang, Bin Ma, Wenya Li, Peiwen Li
Summary: Triple combination therapy for cystic fibrosis patients achieves better clinical results and comparable adverse events compared to the control group.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Genetics & Heredity
Morgan Sanders, James M. J. Lawlor, Xiaopeng Li, John N. Schuen, Susan L. Millard, Xi Zhang, Leah Buck, Bethany Grysko, Katie L. Uhl, David Hinds, Cynthia L. Stenger, Michele Morris, Neil Lamb, Hara Levy, Caleb Bupp, Jeremy W. Prokop
Summary: Studying CFTR variants across diverse populations reveals potential heritable causes of CF and identifies a genomic region that can influence CF pathology through modulation of noncoding RNA expression. This highlights the need for further insights into CF genetics.
Article
Pharmacology & Pharmacy
Jia Liu, Allison P. Berg, Yiting Wang, Walailak Jantarajit, Katy J. Sutcliffe, Edward B. Stevens, Lishuang Cao, Marko J. Pregel, David N. Sheppard
Summary: This study investigates the action of a new CFTR potentiator, CP-628006, and compares it with the marketed CFTR potentiator ivacaftor. CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Lotte Vanherle, Darcy Lidington, Franziska E. Uhl, Saskia Steiner, Stefania Vassallo, Cecilia Skoug, Joao M. N. Duarte, Sangeetha Ramu, Lena Uller, Jean-Francois Desjardins, Kim A. Connelly, Steffen-Sebastian Bolz, Anja Meissner
Summary: Our study investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI) and explored the therapeutic potential of correcting cystic fibrosis transmembrane regulator (CFTR) as an intervention. We found that MI leads to reduced hippocampal dendrite length and spine density, which is associated with decreased neuronal CFTR expression and inflammatory responses. Blocking CFTR activity down-regulates synaptic regulator PSD-95 expression in neurons, while pharmacologically correcting CFTR expression rescues the down-regulation. Increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal structure and memory function. These findings suggest that CFTR therapeutics can attenuate cognitive impairment in heart failure patients.
Review
Biochemistry & Molecular Biology
Laura Carrasco-Hernandez, Esther Quintana-Gallego, Carmen Calero, Rocio Reinoso-Arija, Borja Ruiz-Duque, Jose Luis Lopez-Campos
Summary: The role of CFTR in the pathophysiology of COPD is becoming increasingly important, with its dysfunction leading to thicker and more viscous secretions in the airway, reduced mucociliary clearance, and promotion of airway inflammation. Studying CFTR in the context of COPD pathogenesis is crucial for a comprehensive understanding of COPD's complex pathophysiology and exploring potential therapeutic approaches to address this dysfunction.
Article
Chemistry, Medicinal
Marc J. C. Scanio, Xenia B. Searle, Bo Liu, John R. Koenig, Robert J. Altenbach, Gregory A. Gfesser, Andrew Bogdan, Stephen Greszler, Gang Zhao, Ashvani Singh, Yihong Fan, Andrew M. Swensen, Timothy Vortherms, Arlene Manelli, Corina Balut, Wenqing Gao, Hong Yong, Michael Schrimpf, Chris Tse, Philip Kym, Xueqing Wang
Summary: Cystic fibrosis (CF) is a disease caused by mutations in both copies of the CFTR gene, with the most common mutation being the deletion of phenylalanine at position 508 of the CFTR protein. The most effective treatment for CF currently involves using a combination of CFTR correctors and potentiators. This study focuses on the identification and exploration of the structure-activity relationship of C2 correctors for CFTR, to be used in conjunction with existing C1 correctors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Ho K. Lee, Jinhong Park, Bo-Rahm Kim, Ikhyun Jun, Tae-im Kim, Wan Namkung
Summary: The study identified isorhamnetin as a novel CFTR activator for treating dry eye disease, which increased tear volume and reduced ocular surface damage and inflammatory cytokine expression in an experimental mouse model of dry eye. The findings suggest that isorhamnetin could be a potential therapeutic agent for dry eye disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Eli Fritz McDonald, Jens Meiler, Lars Plate
Summary: Cystic fibrosis is a lethal genetic disease caused by mutations in the CFTR gene. The availability of correctors has greatly improved the treatment of CF in the past decade. However, different mutations show unique responses to drug treatment, highlighting the importance of personalized medicine for CF treatment.
ACS CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Parameet Kumar, Dharmendra Kumar Soni, Chaitali Sen, Mads B. Larsen, Krystyna Mazan-Mamczarz, Yulan Piao, Supriyo De, Myriam Gorospe, Raymond A. Frizzell, Roopa Biswas
Summary: SFPQ expression is reduced in CF lung epithelial cells, but overexpression can increase F508del-CFTR expression and rescue function by modulating cellular signaling pathways. This study is the first to report on the role of SFPQ in regulating the expression and function of F508del-CFTR in CF lung disease, providing insights into potential epigenetic therapeutic targets.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Medicinal
Irene Brusa, Elvira Sondo, Emanuela Pesce, Valeria Tomati, Dario Gioia, Federico Falchi, Beatrice Balboni, Jose Antonio Ortega Martinez, Marina Veronesi, Elisa Romeo, Natasha Margaroli, Maurizio Recanatini, Stefania Girotto, Nicoletta Pedemonte, Marinella Roberti, Andrea Cavalli
Summary: A new RNF5 inhibitor, called 1,2,4-thiadiazol-5-ylidene, has been discovered in this study. It selectively corrects the folding defect of CFTR protein in CF patients and has no toxic side effects. This finding provides evidence for the pursuit of novel treatment strategies for CF.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Respiratory System
Rebecca J. Birch, Daniel Peckham, Henry M. Wood, Philip Quirke, Rob Konstant-Hambling, Keith Brownlee, Rebecca Cosgriff, Nicholas Burr, Amy Downing
Summary: It has been found that individuals with Cystic Fibrosis (CF) have a higher risk of developing colorectal cancer (CRC), and carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations may also face an increased risk. With the increasing life expectancy of CF patients, more individuals are at risk of developing CRC.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Article
Pharmacology & Pharmacy
Kelly M. Martinovich, Anthony Kicic, Stephen M. Stick, Russell D. Johnsen, Sue Fletcher, Steve D. Wilton
Summary: This study aimed to assess the impact of Cftr exon 9 deletion on the mouse CF phenotype. The results showed that Cftr exon 9 deletion in mice led to intestinal obstructions and a decrease in survival rate. Histological examination revealed increased goblet cells and mucus accumulation in the small intestine of Cftr exon 9 deleted mice. Airway epithelial cell cultures from these mice were unresponsive to forskolin stimulation.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Neurosciences
Mark J. Turner, Vinciane Saint-Criq, Waseema Patel, Salam H. Ibrahim, Bernard Verdon, Christopher Ward, James P. Garnett, Robert Tarran, Martin J. Cann, Michael A. Gray
JOURNAL OF PHYSIOLOGY-LONDON
(2016)
Review
Respiratory System
Iram J. Haq, Michael A. Gray, James P. Garnett, Christopher Ward, Malcolm Brodlie
Review
Biochemistry & Molecular Biology
Vinciane Saint-Criq, Michael A. Gray
CELLULAR AND MOLECULAR LIFE SCIENCES
(2017)
Article
Physiology
Salam H. Ibrahim, Mark J. Turner, Vinciane Saint-Criq, James Garnett, Iram J. Haq, Malcolm Brodlie, Chris Ward, Christian Borgo, Mauro Salvi, Andrea Venerando, Michael A. Gray
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2017)
Article
Multidisciplinary Sciences
Michael J. Watson, Shernita L. Lee, Abigail J. Marklew, Rodney C. Gilmore, Martina Gentzsch, Maria F. Sassano, Michael A. Gray, Robert Tarran
SCIENTIFIC REPORTS
(2016)
Article
Biochemistry & Molecular Biology
Waseema Patel, Patrick J. Moore, M. Flori Sassano, Miqueias Lopes-Pacheco, Andrei A. Aleksandrov, Margarida D. Amaral, Robert Tarran, Michael A. Gray
CELLULAR AND MOLECULAR LIFE SCIENCES
(2019)
Editorial Material
Neurosciences
Livia Delpiano, Michael A. Gray
JOURNAL OF PHYSIOLOGY-LONDON
(2019)
Article
Chemistry, Medicinal
Benjamin R. Bellenie, Kwai-Ming J. Cheung, Ana Varela, Olivier A. Pierrat, Gavin W. Collie, Gary M. Box, Michael D. Bright, Sharon Gowan, Angela Hayes, Matthew J. Rodrigues, Kartika N. Shetty, Michael Carter, Owen A. Davis, Alan T. Henley, Paolo Innocenti, Louise D. Johnson, Manjuan Liu, Selby de Klerk, Yann-Vai Le Bihan, Matthew G. Lloyd, P. Craig McAndrew, Erald Shehu, Rachel Talbot, Hannah L. Woodward, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence Raynaud, Olivia W. Rossanese, Swen Hoelder
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Respiratory System
Vinciane Saint-Criq, Yiting Wang, Livia Delpiano, JinHeng Lin, David N. Sheppard, Michael A. Gray
Summary: The presence of extracellular phosphate modulates the function of rescued F508del-CFTR, likely involving electrogenic phosphate transport by SLC34A2. This effect impacts the magnitude of CFTR-mediated Cl- currents and may contribute to the variability in clinical response to CFTR correctors among individuals.
JOURNAL OF CYSTIC FIBROSIS
(2021)
Article
Chemistry, Medicinal
Matthew G. Lloyd, Rosemary Huckvale, Kwai-Ming J. Cheung, Matthew J. Rodrigues, Gavin W. Collie, Olivier A. Pierrat, Mahad Gatti Iou, Michael Carter, Owen A. Davis, P. Craig McAndrew, Emma Gunnell, Yann-Vai Le Bihan, Rachel Talbot, Alan T. Henley, Louise D. Johnson, Angela Hayes, Michael D. Bright, Florence Raynaud, Mirco Meniconi, Rosemary Burke, Rob L. M. van Montfort, Olivia W. Rossanese, Benjamin R. Bellenie, Swen Hoelder
Summary: Optimization of modestly active starting points led to potent inhibitors of BCL6 by perturbing a water network and forming new interactions, ultimately achieving a 100-fold improvement in activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two, showing promising inhibition of BCL6 in cells and satisfactory pharmacokinetic properties for compound 25.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Rosemary Huckvale, Alice C. Harnden, Kwai-Ming J. Cheung, Olivier A. Pierrat, Rachel Talbot, Gary M. Box, Alan T. Henley, Alexis K. de Haven Brandon, Albert E. Hallsworth, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Angela Hayes, Emma A. Gunnell, Alfie Brennan, Owen A. Davis, Louise D. Johnson, Selby de Klerk, Craig McAndrew, Yann-Vai Le Bihan, Mirco Meniconi, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Benjamin R. Bellenie, Swen Hoelder
Summary: This study optimized a benzimidazolone molecular glue-type degrader, leading to the development of a highly potent probe CCT373566 for sustained depletion of BCL6. The research discovered a sharp degradation SAR and demonstrated the impact of subtle structural changes on the ability to induce degradation of BCL6. In a lymphoma xenograft mouse model, CCT373566 showed modest in vivo efficacy following oral dosing.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Owen A. Davis, Kwai-Ming J. Cheung, Alfie Brennan, Matthew G. Lloyd, Matthew J. Rodrigues, Olivier A. Pierrat, Gavin W. Collie, Yann-Vai Le Bihan, Rosemary Huckvale, Alice C. Harnden, Ana Varela, Michael D. Bright, Paul Eve, Angela Hayes, Alan T. Henley, Michael D. Carter, P. Craig McAndrew, Rachel Talbot, Rosemary Burke, Rob L. M. van Montfort, Florence Raynaud, Olivia W. Rossanese, Mirco Meniconi, Benjamin R. Bellenie, Swen Hoelder
Summary: A new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein was identified by ring fusion onto a quinolinone lead series. This was achieved by attaining close shape complementarity and a conformationally restricted core, resulting in potent BCL6 inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Physiology
JinHeng Lin, Sean M. Gettings, Khaoula Talbi, Rainer Schreiber, Michael J. Taggart, Matthias Preller, Karl Kunzelmann, Mike Althaus, Michael A. Gray
Summary: Our study shows that two commonly used CFTR inhibitors, CFTRinh-172 and GlyH-101, significantly inhibit store-operated calcium entry (SOCE) at commonly used concentrations, and this inhibition is independent of CFTR. Patch clamp experiments demonstrate that both inhibitors can reduce SOCE by blocking the CRAC channel. In addition, these inhibitors have significant effects on human alpha beta gamma-ENaC-mediated currents in Xenopus oocytes, but their effects on delta beta gamma-ENaC function differ. Therefore, caution is needed when using these inhibitors to study the physiological role of CFTR and potentially ENaC.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2023)
Article
Multidisciplinary Sciences
Olivier A. Pierrat, Manjuan Liu, Gavin W. Collie, Kartika Shetty, Matthew J. Rodrigues, Yann-Vai Le Bihan, Emma A. Gunnell, P. Craig McAndrew, Mark Stubbs, Martin G. Rowlands, Norhakim Yahya, Erald Shehu, Rachel Talbot, Lisa Pickard, Benjamin R. Bellenie, Kwai-Ming J. Cheung, Ludovic Drouin, Paolo Innocenti, Hannah Woodward, Owen A. Davis, Matthew G. Lloyd, Ana Varela, Rosemary Huckvale, Fabio Broccatelli, Michael Carter, David Galiwango, Angela Hayes, Florence Raynaud, Christopher Bryant, Steven Whittaker, Olivia W. Rossanese, Swen Hoelder, Rosemary Burke, Rob L. M. van Montfort
Summary: By recruiting corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls gene transcription required for B-cell germinal center formation. This study aims to discover small molecule inhibitors that disrupt BCL6-corepressor protein interaction, as BCL6 deregulation is implicated in Diffuse Large B-Cell Lymphoma development. The researchers used high throughput screening and various assays to identify hit series, determined X-ray structures of BCL6 bound to compounds, and developed biochemical and cellular assays to optimize compound potency.
SCIENTIFIC REPORTS
(2022)
Article
Chemistry, Medicinal
Alice C. Harnden, Owen A. Davis, Gary M. Box, Angela Hayes, Louise D. Johnson, Alan T. Henley, Alexis K. de Haven Brandon, Melanie Valenti, Kwai-Ming J. Cheung, Alfie Brennan, Rosemary Huckvale, Olivier A. Pierrat, Rachel Talbot, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Selby de Klerk, Peter Craig McAndrew, Yann-Vai Le Bihan, Mirco Meniconi, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Benjamin R. Bellenie, Swen Hoelder
Summary: In this study, we optimized our previously reported tricyclic quinolinone series to improve the cellular potency and in vivo exposure of the non-degrading isomer, leading to the discovery of a potent BCL6 inhibitor, CCT374705, with good in vivo profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)