Article
Chemistry, Medicinal
Gavin W. Collie, Iacovos N. Michaelides, Kevin Embrey, Christopher J. Stubbs, Ulf Borjesson, Ian L. Dale, Arjan Snijder, Louise Barlind, Kun Song, Puneet Khurana, Christopher Phillips, R. Ian Storer
Summary: A fragment screen targeting the c-MET kinase led to the discovery of inhibitors binding to a rare conformation of the protein, with one inhibitor (7) showing nanomolar biochemical activity against c-MET. These findings enhance our understanding of the folded P-loop conformation of c-MET and provide a basis for further exploration of this potentially therapeutically exploitable state.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Andrew K. Lewis, Abbigael Harthorn, Sadie M. Johnson, Roy R. Lobb, Benjamin J. Hackel
Summary: Researchers have developed a new platform for efficiently engineerable ligands that combine unique pharmacophore activities and shapes. Using this platform, they have discovered a protein-small molecule hybrid that can precisely inhibit carbonic anhydrase. This hybrid exhibits superior efficacy, specificity, and potency compared to traditional drugs and proteins.
CELL CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Microbiology
Han Chen, Ming F. Lye, Christoph Gorgulla, Scott B. Ficarro, Gregory D. Cuny, David A. Scott, Fan Wu, Paul W. Rothlauf, Xiaoou Wang, Rosio Fernandez, Jean M. Pesola, Sorin Draga, Jarrod A. Marto, James M. Hogle, Haribabu Arthanari, Donald M. Coen
Summary: The study found that two small molecule compounds, GK1 and GK2, selectively inhibit the replication of human cytomegalovirus (HCMV) by targeting the nuclear egress complex (NEC). These compounds could serve as a foundation for the development of anti-HCMV drugs and as chemical tools for studying HCMV.
Article
Biochemistry & Molecular Biology
Ulrich Graedler, Daniel Schwarz, Ansgar Wegener, Thomas Eichhorn, Tiago M. Bandeiras, Micael C. Freitas, Alfred Lammens, Oleg Ganichkin, Martin Augustin, Stefano Minguzzi, Frank Becker, Jorg Bomke
Summary: In this study, the researchers investigated the impact of A-loop conformation on the binding of the MET inhibitor tepotinib. They used protein crystallography, biophysical methods, and mass spectrometry to study different recombinant MET kinase domain (KD) protein variants. The results showed that mutations, phosphorylation status, and pi-stacking interactions can affect the residence time of tepotinib. This study provides valuable insights into the structural determinants of the MET A-loop that influence the binding of tepotinib.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biology
Essam Metwally, Victor Mak, Aileen Soriano, Matthias Zebisch, H. Leonardo Silvestre, Paul A. McEwan, Grigori Ermakov, Maribel Beaumont, Paul Tawa, John J. Barker, Rose Yen, Akash Patel, Yeon-Hee Lim, David Healy, Jennifer Hanisak, Alan C. Cheng, Tom Greshock, Thierry O. Fischmann
Summary: This study characterizes and models the cGMP-dependent protein kinase Iα (PKG1α) and its activation mechanism as a homodimer with a small molecule activator. PKG1α is important in regulating smooth muscle function and is a target for treating pulmonary arterial hypertension. Several small molecule compounds capable of activating PKG1α through a cGMP-independent pathway were discovered and their crystal structures showed binding to an allosteric site near the low-affinity nucleotide binding domain. These compounds cause the displacement of the switch helix and activate PKG1α, providing a new mechanism for its control and therapeutic implications.
COMMUNICATIONS BIOLOGY
(2023)
Article
Chemistry, Medicinal
Timothy M. Caldwell, Michael D. Kaufman, Scott C. Wise, Yu Mi Ahn, Molly M. Hood, Wei -Ping Lu, William C. Patt, Thiwanka Samarakoon, Lakshminarayana Vogeti, Subha Vogeti, Karen M. Yates, Stacie L. Bulfer, Bertrand Le Bourdonnec, Bryan D. Smith, Daniel L. Flynn
Summary: A novel series of potent acyl urea-based CSF1R inhibitors were identified, displaying high selectivity for CSF1R versus other members of the receptor tyrosine kinase family. Compound 10 was selected as an advanced lead based on in vitro and in vivo studies.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Immunology
Daniel Schnepf, Stefania Crotta, Thiprampai Thamamongood, Megan Stanifer, Laura Polcik, Annette Ohnemus, Juliane Vier, Celia Jakob, Miriam Llorian, Hans Henrik Gad, Rune Hartmann, Birgit Strobl, Susanne Kirschnek, Steeve Boulant, Martin Schwemmle, Andreas Wack, Peter Staeheli
Summary: Selective TYK2 inhibitors preferentially block potentially detrimental type I interferon signaling while preserving IFN-lambda responses, suggesting a superior treatment option for type I interferonopathies. In contrast, JAK1/2 inhibitors equally block IFN-alpha/beta or IFN-gamma-driven responses.
SCIENCE IMMUNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Ying Xu, Qingfeng Yu, Ping Wang, Zhaoxing Wu, Lei Zhang, Shuigao Wu, Mengyuan Li, Bowen Wu, Hongzhi Li, Haifeng Zhuang, Xuzhao Zhang, Yu Huang, Xiaoxian Gan, Rongzhen Xu
Summary: This study reports a novel oral active molecule glue, WBC100, that selectively degrades c-Myc protein and kills c-Myc overexpressing cancer cells. By targeting a specific region of the c-Myc protein, WBC100 induces protein degradation and apoptosis of cancer cells. In animal models, WBC100 effectively regresses multiple c-Myc overexpressing tumors and exhibits good tolerability. This finding opens new perspectives for pharmacologically targeting the undruggable c-Myc protein in human cancers.
Article
Biochemistry & Molecular Biology
Takamasa Mizoguchi, Shohei Mikami, Mari Yatou, Yui Kondo, Shuhei Omaru, Shuhei Kuwabara, Wataru Okura, Syouta Noda, Takeshi Tenno, Hidekazu Hiroaki, Motoyuki Itoh
Summary: Two small molecules, NPL1010 and NPL3008, have been found to modulate BMP signaling and affect dorsal-ventral patterning and bone formation in zebrafish embryos. They bind to BMP1 and selectively inhibit Chordin cleavage, thereby acting as valuable inhibitors of BMP signaling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Gavin W. Collie, Louise Barlind, Sana Bazzaz, Ulf Borjesson, Ian L. Dale, Jeremy S. Disch, Sevan Habeshian, Rachael Jetson, Puneet Khurana, Andrew Madin, Iacovos N. Michaelides, Ling Peng, Arjan Snijder, Christopher J. Stubbs
Summary: In this study, a highly selective c-MET inhibitor was discovered through screening a DNA-encoded chemical library, and it was found to bind to the kinase in an unprecedented manner as shown by X-ray crystallography. This novel mode of inhibiting c-MET with a small molecule may offer a potential approach to target drug-resistant forms of the kinase while avoiding potential toxicity issues associated with broad kinome inhibition.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Murat Kuecuekdisli, Hassen Bel-Abed, Davide Cirillo, Wen-Ting Lo, Nina-Louisa Efrem, Andre Horatscheck, Liudmila Perepelittchenko, Polina Prokofeva, Theresa A. L. Ehret, Silke Radetzki, Martin Neuenschwander, Edgar Specker, Guillaume Medard, Susanne Mueller, Stephanie Wilhelm, Bernhard Kuster, Jens Peter von Kries, Volker Haucke, Marc Nazare
Summary: Class II phosphoinositide-3-kinases (PI3Ks) have important roles in cell signaling, division, migration, and survival. The lack of isoform-selective inhibitors for PI3K class II isoforms hinders the investigation of their potential as pharmacological targets. In this study, PITCOINs, selective PI3K-C2 alpha inhibitors, were discovered through a structure-activity relationship study. These inhibitors showed high selectivity and no off-target kinase inhibition. This study may contribute to the development of novel therapies for diseases related to PI3K-C2 alpha function.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Cilong Chu, Zixuan Rao, Qingshan Pan, Wufu Zhu
Summary: Small molecule inhibitors targeting c-Met have shown impressive therapeutic efficacy in clinical settings. Recent patents have focused on addressing c-Met amplification and overexpression, highlighting the need for new, safe, efficient, and selective c-Met inhibitors with novel structures to combat bypass secretion and mutagenesis.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2022)
Article
Multidisciplinary Sciences
Min-Ha Choi, Jinhyun Kim, Jeong Hyun Ha, Ji-Ung Park
Summary: PHA-665752 can suppress keloid fibroblast activity by inhibiting the c-Met-related tyrosine kinase pathway. In vivo experiments showed that PHA-665752-treated mice had lower nodule volumes and weights, accompanied by less inflammatory cell infiltration and collagen deposition.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Xia-Wen Dang, Ji-Long Duan, Emily Ye, Nian-Dong Mao, Renren Bai, Xinglu Zhou, Xiang-Yang Ye
Summary: This review summarizes the important role of c-Src kinase in cell division, motility, adhesion, and survival, as well as its implications in disease. It provides valuable insights and new ideas for researchers in areas such as inhibitor development, combination therapy, and clinical research.
BIOORGANIC CHEMISTRY
(2024)
Article
Multidisciplinary Sciences
Hua-Poo Su, Keith Rickert, Christine Burlein, Kartik Narayan, Marina Bukhtiyarova, Danielle M. Hurzy, Craig A. Stump, Xufang Zhang, John Reid, Alicja Krasowska-Zoladek, Srivanya Tummala, Jennifer M. Shipman, Maria Kornienko, Peter A. Lemaire, Daniel Krosky, Amanda Heller, Abdelghani Achab, Chad Chamberlin, Peter Saradjian, Berengere Sauvagnat, Xianshu Yang, Michael R. Ziebell, Elliott Nickbarg, John M. Sanders, Mark T. Bilodeau, Steven S. Carroll, Kevin J. Lumb, Stephen M. Soisson, Darrell A. Henze, Andrew J. Cooke
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2017)
Article
Chemistry, Medicinal
Jonathan M. Blevitt, Michael D. Hack, Krystal L. Herman, Paul F. Jackson, Paul J. Krawczuk, Alec D. Lebsack, Annie X. Liu, Taraneh Mirzadegan, Marina I. Nelen, Aaron N. Patrick, Stefan Steinbacher, Marcos E. Milla, Kevin J. Lumb
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Multidisciplinary Sciences
Haitao Zhang, Gye Won Han, Alexander Batyuk, Andrii I. Shchenko, Kate L. White, Nilkanth Patel, Anastasiia Sadybekov, Beata Zamlynny, Michael T. Rudd, Kaspar Hollenstein, Alexandra Tolstikova, Thomas A. White, Mark S. Hunter, Uwe Weierstall, Wei Liu, Kerim Babaoglu, Eric L. Moore, Ryan D. Katz, Jennifer M. Shipman, Margarita Garcia-Calvo, Sujata Sharma, Payal Sheth, Stephen M. Soisson, Raymond C. Stevens, Vsevolod Katritch, Vadim C. Herezov
Article
Biochemistry & Molecular Biology
Nathaniel L. Elsen, Sangita B. Patel, Rachael E. Ford, Dawn L. Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M. Shipman, Sujata Sharma, Kevin J. Lumb, Stephen M. Soisson, Daniel J. Klein
NATURE CHEMICAL BIOLOGY
(2017)
Article
Biochemistry & Molecular Biology
Jun Lu, Noel Byrne, John Wang, Gerard Bricogne, Frank K. Brown, Harry R. Chobanian, Steven L. Colletti, Jerry Di Salvo, Brande Thomas-Fowlkes, Yan Guo, Dawn L. Hall, Jennifer Hadix, Nicholas B. Hastings, Jeffrey D. Hermes, Thu Ho, Andrew D. Howard, Hubert Josien, Maria Kornienko, Kevin J. Lumb, Michael W. Miller, Sangita B. Patel, Barbara Pio, Christopher W. Plummer, Bradley S. Sherborne, Payal Sheth, Sarah Souza, Srivanya Tummala, Clemens Vonrhein, Maria Webb, Samantha J. Allen, Jennifer M. Johnston, Adam B. Weinglass, Sujata Sharma, Stephen M. Soisson
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2017)
Article
Biochemistry & Molecular Biology
Jun Lu, Noel Byrne, John Wang, Gerard Bricogne, Frank K. Brown, Harry R. Chobanian, Steven L. Colletti, Jerry Di Salvo, Brande Thomas-Fowlkes, Yan Guo, Dawn L. Hall, Jennifer Hadix, Nicholas B. Hastings, Jeffrey D. Hermes, Thu Ho, Andrew D. Howard, Hubert Josien, Maria Kornienko, Kevin J. Lumb, Michael W. Miller, Sangita B. Patel, Barbara Pio, Christopher W. Plummer, Bradley S. Sherborne, Payal Sheth, Sarah Souza, Srivanya Tummala, Clemens Vonrhein, Maria Webb, Samantha J. Allen, Jennifer M. Johnston, Adam B. Weinglass, Sujata Sharma, Stephen M. Soisson
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2017)
Article
Chemistry, Medicinal
Shawn J. Stachel, Anthony T. Ginnetti, Scott A. Johnson, Paige Cramer, Yi Wang, Marina Bukhtiyarova, Daniel Krosky, Craig Stump, Danielle M. Hurzy, Kelly-Ann Schlegel, Andrew J. Cooke, Samantha Allen, Gregory O'Donnell, Michael Ziebell, Gopal Parthasarathy, Krista L. Getty, Thu Ho, Yangsi Ou, Aneta Jovanovska, Steve S. Carroll, Mark Pausch, Kevin Lumb, Scott D. Mosser, Bhavya Voleti, Daniel J. Klein, Stephen M. Soisson, Celina Zerbinatti, Paul J. Coleman
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Multidisciplinary Sciences
Chuan Hong, Noel J. Byrne, Beata Zamlynny, Srivanya Tummala, Li Xiao, Jennifer M. Shipman, Andrea T. Partridge, Christina Minnick, Michael J. Breslin, Michael T. Rudd, Shawn J. Stachel, Vanessa L. Rada, Jeffrey C. Kern, Kira A. Armacost, Scott A. Hollingsworth, Julie A. O'Brien, Dawn L. Hall, Terrence P. McDonald, Corey Strickland, Alexei Brooun, Stephen M. Soisson, Kaspar Hollenstein
Summary: NT1 is a chronic neurological disorder with limited treatment options, while OX2R agonists show promise in providing novel therapeutic approaches. Cryo-EM structures of OX2R bound to agonists suggest a molecular mechanism for receptor activation and inhibition.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Whitney L. Petrilli, Gregory C. Adam, Roman S. Erdmann, Pravien Abeywickrema, Vijayalakshmi Agnani, Xi Ai, Jen Baysarowich, Noel Byrne, John P. Caldwell, Wonsuk Chang, Edward DiNunzio, Zhe Feng, Rachael Ford, Sookhee Ha, Yongcheng Huang, Brian Hubbard, Jennifer M. Johnston, Michael Kavana, Jean-Marie Lisnock, Rui Liang, Jun Lu, Zhijian Lu, Juncai Meng, Peter Orth, Oksana Palyha, Gopal Parthasarathy, Scott P. Salowe, Sujata Sharma, Jennifer Shipman, Stephen M. Soisson, Alison M. Strack, Hyewon Youm, Kake Zhao, Deborah L. Zink, Hratch Zokian, George H. Addona, Karen Akinsanya, James R. Tata, Yusheng Xiong, Jason E. Imbriglio
CELL CHEMICAL BIOLOGY
(2020)
Meeting Abstract
Biochemistry & Molecular Biology
Srivanya Tummala, Noel Byrne, Jennifer Shipman, James Kostas, Richard Edwards, Kaspar Hollenstein, Harini Krishnamurthy, Alexei Brooun, Stephen Soisson
Meeting Abstract
Biochemistry & Molecular Biology
Michael Eddins, Hua-poo Su, Xiao Xiao, Jennifer Shipman, Srivanya Tummala, John Reid, Yacob Gomez Llorente, Zhifeng Chen, Eberhard Durr, James Cook, Kerim Babaoglu, Stephen Soisson, Lan Zhang, Kalpit Vora, Alexei Brooun
Article
Biochemical Research Methods
Victoria D. Kutilek, Christine L. Andrews, Matthew P. Richards, Zangwei Xu, Tianxiao Sun, Yiping Chen, Andrew Hashke, Nadya Smotrov, Rafael Fernandez, Elliott B. Nickbarg, Chad Chamberlin, Berengere Sauvagnat, Patrick J. Curran, Ryan Boinay, Peter Saradjian, Samantha J. Allen, Noel Byrne, Nathaniel L. Elsen, Rachael E. Ford, Dawn L. Hall, Maria Kornienko, Keith W. Rickert, Sujata Sharma, Jennifer M. Shipman, Kevin J. Lumb, Kevin Coleman, Peter J. Dandliker, Ilona Kariv, Bruce Beutel
JOURNAL OF BIOMOLECULAR SCREENING
(2016)