Article
Chemistry, Medicinal
Zachary W. Davis-Gilbert, Andreas Kraemer, James E. Dunford, Stefanie Howell, Filiz Senbabaoglu, Carrow I. Wells, Frances M. Bashore, Tammy M. Havener, Jeffery L. Smith, Mohammad A. Hossain, Udo Oppermann, David H. Drewry, Alison D. Axtman
Summary: Naphthyridine-based inhibitors were synthesized to produce a potent and cell active inhibitor of casein kinase 2 (CK2). Compound 2 selectively inhibits CK2 alpha and CK2 alpha ' when broad-profiled, making it an exquisitely selective chemical probe for CK2. A negative control, compound 7, lacking a key hinge-binding nitrogen, was designed based on structural studies and showed excellent kinome-wide selectivity by not binding CK2 alpha or CK2 alpha ' in cells. Compound 2 displayed differential anticancer activity compared to a structurally distinct CK2 chemical probe, SGC-CK2-1.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Multidisciplinary Sciences
Heather Mahoney, Emily Peterson, Hannah Justin, David Gonzalez, Christopher Cardona, Korey Stevanovic, John Faulkner, Amara Yunus, Alexandra Portugues, Amy Henriksen, Camden Burns, Cameron McNeill, Joshua Gamsby, Danielle Gulick
Summary: Time-of-day effects have been observed in cognitive behavioral tests, and disruption of the circadian system can impair hippocampus-dependent learning and memory. Modulation of circadian kinases, such as CK1 delta/epsilon, presents a novel approach for improving cognitive deficits. The inhibitor PF-670462 showed potential in enhancing cognitive performance in mice, suggesting the utility of CK1 delta/epsilon inhibition in improving time-of-day cognitive performance.
SCIENTIFIC REPORTS
(2021)
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)
Article
Chemistry, Medicinal
Rachel A. Rowlands, Qiuyan Chen, Renee A. Bouley, Larisa Avramova, John J. G. Tesmer, Andrew D. White
Summary: The ability of GRK2 and GRK5 to regulate GPCR desensitization makes them attractive targets for heart failure and cancer treatment. Previous research showed potential for selective inhibition of GRK5 over GRK2 using a specific residue, but the inhibitors were not very potent. A new study successfully adapted an indolinone scaffold with covalent warheads, creating compounds with high selectivity for GRK5 and low nanomolar potency.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Min Li, Dario Oliveira Passos, Zelin Shan, Steven J. Smith, Qinfang Sun, Avik Biswas, Indrani Choudhuri, Timothy S. Strutzenberg, Allan Haldane, Nanjie Deng, Zhaoyang Li, Xue Zhi Zhao, Lorenzo Briganti, Mamuka Kvaratskhelia, Terrence R. R. Burke Jr, Ronald M. Levy, Stephen H. Hughes, Robert Craigie, Dmitry Lyumkis
Summary: A new drug (4d) was found to be more effective in inhibiting drug-resistant HIV-1 mutants that develop resistance to INSTIs compared to the approved drug (DTG). By using cryo-EM structures and free energy simulations, the mechanisms of DTG resistance and why 4d maintains its potency better than DTG were explained.
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
Biology
Kangcheng Song, Miao Wei, Wenjun Guo, Li Quan, Yunlu Kang, Jing-Xiang Wu, Lei Chen
Summary: TRPC5 channel is a nonselective cation channel involved in various physiological processes. Inhibitors of TRPC5, such as clemizole and HC-070, stabilize the ion channel in a nonconductive closed state, potentially offering new therapeutic strategies for anxiety disorders, depression, and kidney diseases. The cryo-EM structures of human TRPC5 with inhibitors provide insights into the binding sites and inhibitory mechanisms, facilitating the development of more effective inhibitors targeting TRPC5.
Article
Cell Biology
Carolyn M. Kelly, Laura J. Byrnes, Niharika Neela, Holger Sondermann, John P. O'Donnell
Summary: Research has identified the critical role of the N-terminal hypervariable region (HVR) in ATL proteins in membrane fusion, with regulation through phosphorylation-dependent modification. The structural features of HVR positively impact membrane tethering and cellular function of ATLs, laying the foundation for identifying cellular effectors of ATL-mediated membrane processes.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Rostom Ahmed-Belkacem, Marcel Hausdorff, Adrien Delpal, Priscila Sutto-Ortiz, Agathe M. G. Colmant, Franck Touret, Natacha S. Ogando, Eric J. Snijder, Bruno Canard, Bruno Coutard, Jean-Jacques Vasseur, Etienne Decroly, Francoise Debart
Summary: This study focuses on the design and synthesis of inhibitors against SARS-CoV-2 enzymes involved in RNA capping, which are important for viral RNA stability, mRNA translation, and evasion of innate immunity. Seven compounds showed significant inhibitory activity, and the three most potent inhibitors stabilized the enzyme effectively.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xiaofei Liang, Chun Wang, Beilei Wang, Juan Liu, Shuang Qi, Aoli Wang, Qingwang Liu, Maoqing Deng, Li Wang, Jing Liu, Qingsong Liu
Summary: CSF1R kinase is crucial in tumor-associated macrophage repolarization, and the selective inhibitor 18h shows potent inhibition against CSF1R with significant selectivity, leading to suppression of tumor growth.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yun Wu, Ziping Qi, Beilei Wang, Junjie Wang, Qingwang Liu, Aoli Wang, Chenliang Shi, Bin Zhou, Qianmao Liang, Wenliang Wang, Fengming Zou, Shuang Qi, Zuowei Wang, Li Wang, Wenchao Wang, Jing Liu, Qingsong Liu
Summary: A novel, potent, and selective MST1 inhibitor 19 was discovered, which protected ss cells from inflammatory cytokines in vitro and showed potential in treating diabetes in animal models.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yuanjiang Wang, Zhaodan Lv, Feihong Chen, Xing Wang, Shaohua Gou
Summary: The synthesized molecule 1c has strong CK2 inhibitory activity and high selectivity, as well as the ability to modulate key signaling pathways and inhibit the expression of stem markers, showing potent inhibitory activity against cancer stem cells, making it a potential candidate for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Alexander Sokolsky, Oleg Vechorkin, Joshua R. Hummel, Evan D. Styduhar, Anlai Wang, Minh H. Nguyen, Hai Fen Ye, Kai Liu, Ke Zhang, Jun Pan, Qinda Ye, Onur Atasoylu, Elham Behshad, Xin He, Patricia Conlen, Kristine Stump, Min Ye, Sharon Diamond, Maryanne Covington, Swamy Yeleswaram, Wenqing Yao
Summary: A novel biaryl amide series has been discovered as selective inhibitors of HPK1, showing outstanding enzymatic and cellular potency and encouraging kinome selectivity.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
John M. Ketcham, Jacob Haling, Shilpi Khare, Vickie Bowcut, David M. Briere, Aaron C. Burns, Robin J. Gunn, Anthony Ivetac, Jon Kuehler, Svitlana Kulyk, Jade Laguer, J. David Lawson, Krystal Moya, Natalie Nguyen, Lisa Rahbaek, Barbara Saechao, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Laura Vegar, Darin Vanderpool, Xiaolun Wang, Larry Yan, Peter Olson, James G. Christensen, Matthew A. Marx
Summary: SOS1 is an important regulator of KRAS, and disrupting the SOS1:KRASG12C protein-protein interaction can increase the proportion of GDP-loaded KRASG12C. In this study, researchers designed and discovered MRTX0902, a potent and selective SOS1 binder that can disrupt the SOS1:KRASG12C interaction. Combining oral administration of MRTX0902 with MRTX849 has shown significant antitumor activity, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jonathan M. Philpott, Alfred M. Freeberg, Jiyoung Park, Kwangjun Lee, Clarisse G. Ricci, Sabrina R. Hunt, Rajesh Narasimamurthy, David H. Segal, Rafael Robles, Yao Cai, Sarvind Tripathi, J. Andrew McCammon, David M. Virshup, Joanna C. Chiu, Choogon Lee, Carrie L. Partch
Summary: The PERIOD (PER) and Casein Kinase 18 play a crucial role in regulating circadian rhythms by controlling PER stability and repressive activity. Phosphorylation of the FASP serine cluster in PER1/2 by CK18 inhibits its activity, stabilizes PER, and extends the circadian period. The study also reveals a conserved feedback inhibition mechanism between Drosophila PER and CK18.