Article
Chemistry, Multidisciplinary
Robert P. Law, Joao Nunes, Chun-wa Chung, Marcus Bantscheff, Karol Buda, Han Dai, John P. Evans, Adam Flinders, Diana Klimaszewska, Antonia J. Lewis, Marcel Muelbaier, Paul Scott-Stevens, Peter Stacey, Christopher J. Tame, Gillian F. Watt, Nico Zinn, Markus A. Queisser, John D. Harling, Andrew B. Benowitz
Summary: This study introduced a novel FAK-degrading PROTAC, GSK215, designed based on VHL E3 ligase and the FAK inhibitor VS-4718, showing promising potential for a differentiated clinical strategy in cancer treatment compared to conventional FAK inhibition. The highly cooperative FAK-GSK215-VHL ternary complex revealed by X-ray crystallography provided insights into the molecular basis of the compound's efficacy. In mouse models, GSK215 demonstrated rapid and prolonged FAK degradation, highlighting its potential as a valuable tool for studying FAK-degradation biology in vivo.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Amjad Ali, Marcus Bauser, Sophie Bertrand, Wesley Blackaby, Christoph Boss, Martin Bossart, Adrian Hall, Hayley Binch, Werngard Czechtizky, Harrie Gijsen, Helmut Haning, Ingo V. Hartung, Paul Kilburn, Gilbert Lassalle, Ulrich Luecking, Juergen Mack, Martin Missbach, Leena Otsomaa, Antoni Torrens, Michael Wagner, Magnus Walter, Harald Weinstabl, Luc van Hijfte, Franz von Nussbaum
Summary: This article discusses the status of industrial Medicinal Chemistry, with emphasis on the expansion of the chemical modality space and the increasing importance of "greenness" in drug molecule optimization. The pharmaceutical discovery ecosystem has significantly evolved, with the emergence of new key players such as Biotech and integrated CROs as well as Digital companies. However, the impact of digitalization on project speed and success rates has been limited. Future Medicinal Chemists must excel in synthetic chemistry and possess knowledge in new computational areas, while also demonstrating strong collaboration and teamwork skills.
Article
Chemistry, Multidisciplinary
Jenny Desantis, Andrea Mammoli, Michela Eleuteri, Alice Coletti, Federico Croci, Antonio Macchiarulo, Laura Goracci
Summary: Proteolysis targeting chimeras (PROTACs) are a class of compounds with innovative therapeutic applications, which can induce ubiquitination and degradation of target proteins. Designing PROTACs with improved physicochemical and pharmacokinetic properties is still a challenging task. In this study, the impact of fine modulation of piperazine-containing linkers on the protonation state of PROTACs and similar heterobifunctional compounds was evaluated, and the possibility of predicting trends through in silico approaches was investigated.
Article
Chemistry, Medicinal
Alessio Ciulli, Suzanne O'Connor, Chun-Wa Chung, Ingo V. Hartung, Andrea Testa, Danette L. Daniels, Laura H. Heitman
Summary: This report provides an overview of the 17th EFMC Short Course on Medicinal Chemistry, highlighting the inclusion of the exciting topic of Targeted Protein Degradation. It summarizes the successful event and key lectures, as well as the diverse representation of attendees from Europe, the US, and South Africa.
Review
Medicine, Research & Experimental
Xiaojuan Jia, Xin Han
Summary: Inhibition of androgen receptor (AR) has been extensively studied for treating prostate cancer, but resistance mechanisms limit its efficacy. Small-molecule PROTAC AR degraders have emerged as a new therapeutic strategy to overcome resistance mechanisms. In the last two decades, potent PROTAC AR degraders have shown promising results in preclinical and clinical trials, with ARV-110 demonstrating good clinical effects in patients with mCRPC. This highlights the high clinical value of PROTAC strategy in treating human diseases. This review summarizes the recent advances in the development of potential clinical-stage PROTAC AR degraders.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Review
Biochemistry & Molecular Biology
Poornachandra Yedla, Ahmed O. Babalghith, Vindhya Vasini Andra, Riyaz Syed
Summary: Cancer treatments with targeted therapy, specifically Proteolysis-Targeting Chimeras (PROTACs), have gained significant attention for their unique mechanism of action and ability to target undruggable proteins. This review focuses on PROTACs in prostate cancer, highlighting their superiority over conventional inhibitors, and discussing the challenges and future prospects in this field. It also explores the underlying pathophysiology of prostate cancer and provides insights into the structural design and linker strategies for PROTAC molecules.
Review
Chemistry, Medicinal
Daniel Schaefer, Xinlai Cheng
Summary: Despite the increasing number of biologics license applications, the development of covalent inhibitors remains a growing field in drug discovery. The successful approval of certain covalent protein kinase inhibitors and the recent discovery of covalent inhibitors for viral proteases represent advancements in covalent drug development. Covalent bonds targeting proteins offer advantages in target selectivity, drug resistance, and administration concentration. The electrophile (warhead) is a crucial factor for covalent inhibitors, dictating selectivity and reactivity, and can be modified through rational designs. Covalent inhibitors are also finding applications in protein degradation and targeting chimeras (PROTACs) for 'undruggable' proteins, as well as in the treatment of SARS-CoV-2.
Review
Chemistry, Medicinal
Ri Han, Hongryul Yoon, Gahee Kim, Hyundo Lee, Yoonji Lee
Summary: This review article explores the application of artificial intelligence in medicinal chemistry, specifically focusing on the use of machine learning and deep learning techniques in drug screening and design. Research has shown that artificial intelligence can accelerate the drug discovery process and has great potential in predicting and understanding drug interactions and properties. However, data quality issues and technological constraints remain challenges that require interdisciplinary collaboration to fully realize its potential.
Review
Chemistry, Medicinal
Anna Pasieka, Eleonora Diamanti, Elisa Uliassi, Maria Laura Bolognesi
Summary: Click chemistry and targeted protein degradation, two flourishing trends in medicinal chemistry. Can they be a winning combination? In this review, we provide the reader with selected examples offered by the combination of these two approaches trying to find a response to this question.
Review
Chemistry, Multidisciplinary
Xin Han, Yi Sun
Summary: This review focuses on the discovery and development of orally available anti-cancer PROTAC degraders, summarizing the strategies applied to this end, which may provide a reference for the future discovery of new oral-available PROTAC degraders for the treatment of various human diseases.
CELL REPORTS PHYSICAL SCIENCE
(2022)
Article
Chemistry, Medicinal
Yan Li, Jian Song, Ping Zhou, Jun Zhou, Songbo Xie
Summary: Dysregulation of transcription factors is implicated in various human diseases, but these proteins have been traditionally considered undruggable. However, proteolysis-targeting chimeras (PROTACs) have shown great promise in overcoming drug resistance and targeting previously undruggable proteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Correction
Chemistry, Multidisciplinary
Christine N. Morrison, Kathleen E. Prosser, Ryjul W. Stokes, Anna Cordes, Nils Metzler-Nolte, Seth M. Cohen
Summary: Correction issued for the article titled "Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery" by Christine N. Morrison et al., Chem. Sci., 2020, 11, 1216-1225, https://doi.org/10.1039/C9SC05586J.
Correction
Chemistry, Multidisciplinary
Christine N. Morrison, Kathleen E. Prosser, Ryjul W. Stokes, Anna Cordes, Nils Metzler-Nolte, Seth M. Cohen
Summary: The study introduces a novel approach using metallofragments as 3D scaffolds for fragment-based drug discovery. This method has great potential in the field of medicinal chemistry and provides a new direction for drug development.
Article
Biochemistry & Molecular Biology
Jian-Jia Liang, Hang Xie, Rui-Hua Yang, Ni Wang, Zi-Jun Zheng, Chen Zhou, Ya-Lei Wang, Zhi-Jia Wang, Hong-Min Liu, Li-Hong Shan, Yu Ke
Summary: In this study, novel PROTACs containing different linker phthalimide degrons were designed, synthesized, and evaluated for their AR degradation activity. Compound A16 showed the best AR binding affinity and degradation activity, while B10 exhibited effective internalization and visualization in LNCaP cells. Molecular docking of A16 with AR and the DDB1-CRBN E3 ubiquitin ligase complex provides guidance for designing new PROTAC degrons targeting AR in prostate cancer therapy. This research represents progress towards developing novel and improved AR PROTACs.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Haixia Liu, Qianglong Mi, Xinyu Ding, Chencen Lin, Linyi Liu, Chaowei Ren, ShuTing Shen, YuBao Shao, Jinju Chen, Yongqi Zhou, Liting Ji, Heqiao Zhang, Fang Bai, Xiaobao Yang, Qianqian Yin, Biao Jiang
Summary: In this study, a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL were synthesized, and compound 30 (SIAIS100) was discovered to be the most potent degrading agent against BCR-ABL. The compound exhibited sustained efficacy for 96 hours post-washout and showed degradative activity against various clinically relevant resistance-conferring mutations of BCR-ABL.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Elliott D. Bayle, Fredrik Svensson, Benjamin N. Atkinson, David Steadman, Nicky J. Willis, Hannah L. Woodward, Paul Whiting, Jean-Paul Vincent, Paul Fish
Summary: Regulation of the Wnt signaling pathway is crucial for various cellular processes in both development and adult mammalian biology. Inhibiting Notum activity may provide a new approach for treating diseases where aberrant Notum activity is the underlying cause. Reliable screening technologies and structural studies are accelerating the discovery of new Notum inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Michael Brand, James Clayton, Mustafa Moroglu, Matthias Schiedel, Sarah Picaud, Joseph P. Bluck, Anna Skwarska, Hannah Bolland, Anthony K. N. Chan, Corentine M. C. Laurin, Amy R. Scorah, Larissa See, Timothy P. C. Rooney, Katrina H. Andrews, Oleg Fedorov, Gabriella Perell, Prakriti Kalra, Kayla B. Vinh, Wilian A. Cortopassi, Pascal Heitel, Kirsten E. Christensen, Richard Cooper, Robert S. Paton, William C. K. Pomerantz, Philip C. Biggin, Ester M. Hammond, Panagis Filippakopoulos, Stuart J. Conway
Summary: CREBBP and EP300 are lysine acetyltransferases essential for human development, interacting with numerous proteins as important transcriptional co-activators and key nodes in the human protein-protein interactome. Inhibition of the CREBBP/EP300 bromodomains leads to reduced c-Myc levels and decreased acetylation of H3K18 and H3K27, with enhanced stabilization of HIF-1 alpha in hypoxic conditions.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Helen K. Boffey, Timothy P. C. Rooney, Henriette M. G. Willems, Simon Edwards, Christopher Green, Tina Howard, Derek Ogg, Tamara Romero, Duncan E. Scott, David Winpenny, James Duce, John Skidmore, Jonathan H. Clarke, Stephen P. Andrews
Summary: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are promising therapeutic targets in diseases such as cancer, immunological disorders, and neurodegeneration. In this study, the physicochemical properties of a selective PI5P4K gamma inhibitor were improved, enabling its interaction with PI5P4K gamma in intact cells without inhibiting PI5P4K alpha or PI5P4K beta. The X-ray structure of PI5P4K gamma bound to an inhibitor revealed an allosteric binding mode.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
David Norton, William G. Bonnette, James F. Callahan, Maria G. Carr, Charlotte M. Griffiths-Jones, Tom D. Heightman, Jeffrey K. Kerns, Hong Nie, Sharna J. Rich, Caroline Richardson, William Rumsey, Yolanda Sanchez, Marcel L. Verdonk, Henriette M. G. Willems, William E. Wixted, Lawrence Wolfe, Alison J-A Woolford, Zining Wu, Thomas G. Davies
Summary: This study explores a novel approach to develop KEAP1 inhibitors using fragment-based drug discovery, identifying new hit matter through database searching and optimizing lead compounds, providing a new perspective for developing drugs to treat diseases involving chronic oxidative stress.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Neurosciences
Angeleen Fleming, Mathieu Bourdenx, Motoki Fujimaki, Cansu Karabiyik, Gregory J. Krause, Ana Lopez, Claudia Puri, Aurora Scrivo, John Skidmore, Sung Min Son, Eleanna Stamatakou, Lidia Wrobel, Ye Zhu, Ana Maria Cuervo, David C. Rubinsztein
Summary: Autophagy is crucial for maintaining cellular homeostasis by degrading proteins and organelles. The nervous system is particularly dependent on these pathways, which may become less effective with age. Autophagy pathways play a protective role in neurodegenerative diseases and are also linked to different types of programmed cell death.
Article
Chemistry, Medicinal
Nicky J. Willis, William Mahy, James Sipthorp, Yuguang Zhao, Hannah L. Woodward, Benjamin N. Atkinson, Elliott D. Bayle, Fredrik Svensson, Sarah Frew, Fiona Jeganathan, Amy Monaghan, Stefano Benvegnu, Sarah Jolly, Luca Vecchia, Reinis R. Ruza, Svend Kjaer, Steven Howell, Ambrosius P. Snijders, Magda Bictash, Patricia C. Salinas, Jean-Paul Vincent, E. Yvonne Jones, Paul Whiting, Paul Fish
Summary: Notum functions as a crucial enzyme in human diseases such as colorectal cancer and Alzheimer's disease. The discovery of 8l as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease marks a significant progress in developing improved inhibitors for neurodegenerative diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Timothy P. C. Rooney, Gregory G. Aldred, Helen K. Boffey, Henriette M. G. Willems, Simon Edwards, Stephen J. Chawner, Duncan E. Scott, Christopher Green, David Winpenny, John Skidmore, Jonathan H. Clarke, Stephen P. Andrews
Summary: Due to their crucial role in regulating cell signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) hold promise as therapeutic targets for cancer, neurodegeneration, and immunological disorders. However, the availability of potent and isoform-selective tool molecules for these kinases has been limited, hindering further investigation in biology and drug development.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Henriette M. G. Willems, Simon Edwards, Helen K. Boffey, Stephen J. Chawner, Christopher Green, Tamara Romero, David Winpenny, John Skidmore, Jonathan H. Clarke, Stephen P. Andrews
Summary: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a crucial role in regulating cell signaling pathways, making them potential therapeutic targets for various diseases. However, the current PI5P4Ka inhibitors lack selectivity and potency. In this study, we identified a novel PI5P4Ka inhibitor through virtual screening, which showed high potency, selectivity, and broad activity against lipid and protein kinases. Detailed data on ADMET, target engagement, and X-ray structure were provided.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Duncan E. Scott, Nicola J. Francis-Newton, May E. Marsh, Anthony G. Coyne, Gerhard Fischer, Tommaso Moschetti, Andrew R. Bayly, Timothy D. Sharpe, Kalina T. Haas, Lorraine Barber, Chiara R. Valenzano, Rajavel Srinivasan, David J. Huggins, Miyoung Lee, Amy Emery, Bryn Hardwick, Matthias Ehebauer, Claudio Dagostin, Alessandro Esposito, Luca Pellegrini, Trevor Perrior, Grahame McKenzie, Tom L. Blundell, Marko Hyvonen, John Skidmore, Ashok R. Venkitaraman, Chris Abell
Summary: The study identifies CAM833 as an orthosteric inhibitor of RAD51:BRC, which affects DNA repair and potentiates cell death induced by DNA damage, working in coordination with PARP1 inhibitors to suppress growth in BRCA2-wildtype cells.
CELL CHEMICAL BIOLOGY
(2021)
Article
Oncology
Karen D. Howarth, Tashfina Mirza, Susanna L. Cooke, Suet-Feung Chin, Jessica C. Pole, Ernest Turro, Matthew D. Eldridge, Raquel Manzano Garcia, Oscar M. Rueda, Chris Boursnell, Jean E. Abraham, Carlos Caldas, Paul A. W. Edwards
Summary: NRG1 gene fusions in breast cancer exhibit complexity, with some fusions being inactivating rather than activating. Careful interpretation of NRG1 rearrangements will be crucial for appropriate patient management.
BREAST CANCER RESEARCH
(2021)
