Article
Biochemistry & Molecular Biology
Xumei Liu, Qiong Shi, Namrta Choudhry, Ting Zhang, Hong Liu, Shenqiu Zhang, Jing Zhang, Dun Yang
Summary: Small molecule inhibitors of aurora kinases are being investigated for their potential role in cancer treatment. This study focused on the effects of a reversible pan-aurora kinase inhibitor, VX-680, on normal human cells. The researchers found that VX-680 could block cell division and induce cell arrest, but a fraction of normal cells were able to resume proliferation after treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Michael A. Hadders, Susanne M. A. Lens
Summary: The Chromosomal Passenger Complex (CPC) is a crucial protein complex that regulates various processes during nuclear and cytoplasmic division. It is recruited to centromeres and kinetochores in early mitosis to ensure proper connection of duplicated chromosomes to microtubules. During anaphase, the CPC is relocated to the microtubule overlaps and equatorial cortex, requiring direct interactions with a kinesin-6 family member and inactivation of cyclin B-CDK1.
TRENDS IN CELL BIOLOGY
(2022)
Article
Genetics & Heredity
Charlotte S. Repton, C. Fiona P. Cullen, Mariana F. A. S. Costa, Christos P. Spanos, Juri S. Rappsilber, Hiroyuki P. Ohkura
Summary: This study reveals the important role of 14-3-3 protein in regulating multiple microtubule-associated proteins in fly oocytes. The interaction between 14-3-3 and one of the subunits is regulated by phosphorylations, which are crucial for localization and function of the subunit. As these proteins are conserved in many species, including humans, this study may provide insight into chromosome mis-segregation in human oocytes, which is a major cause of human infertility, miscarriages, and congenital birth conditions.
Review
Biochemistry & Molecular Biology
Antal H. Kovacs, Dong Zhao, Jinqiang Hou
Summary: This paper presents a comprehensive review of the preclinical and clinical candidates of Aurora B inhibitors as potential anticancer drugs. The recent advances in the field of Aurora B inhibitor development will be highlighted, and the binding interactions between Aurora B and inhibitors based on crystal structures will be presented and discussed to provide insights for the future design of more selective Aurora B inhibitors.
Article
Biology
Jian Li, Xinli Ma, Surajit Banerjee, Hanyong Chen, Weiya Ma, Ann M. Bode, Zigang Dong
Summary: Mutations in the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) affect their binding abilities, providing insights and directions for rational drug design.
COMMUNICATIONS BIOLOGY
(2021)
Article
Multidisciplinary Sciences
S. M. Naimul Hasan, Jennifer W. W. Lou, Alexander F. A. Keszei, David L. L. Dai, Mohammad T. T. Mazhab-Jafari
Summary: The authors developed a protein engineering method to study the structure of human fatty acid synthase. They discovered unique structural features of the enzyme and its inhibition mechanism by an anticancer drug. Fatty acid synthase is an important target in various diseases.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Jimin Li, Fang Yang, Zeyu Wang, Siqing Zheng, Shuang Zhang, Chen Wang, Bing He, Jia-Bei Wang, Hao Wang
Summary: The RNA m6A methyltransferase METTL16 plays a crucial role in chromosome segregation and stability in colorectal cancer cells. It promotes mitotic progression through the m6A-dependent enhancement of Soga1 expression. Targeting the METTL16-Soga1 pathway may be a potential strategy for treating CRC.
CELL PROLIFERATION
(2023)
Article
Oncology
Jieun Kim, Jun-Young Lee, Suk-Youl Park, You Jeong Lee, Min-Sung Kim
Summary: Immunotherapy using IL-2 to activate anti-tumor immune response shows promise for cancer treatment by amplifying the activity in effector T cells. A novel IL-2Rα mimetic antibody, TCB2, has been developed to specifically stimulate T effector cells when combined with hIL-2, leading to potent anti-cancer effects. Structural analysis of TCB2 binding to hIL-2 reveals a different binding angle and epitope compared to previously known antibodies, resulting in increased affinity for the hetero-dimeric hIL-2 receptor on effector T cells.
Article
Biology
Elsie Diaz, Suraj Adhikary, Armand W. J. W. Tepper, Daniel Riley, Rodrigo Ortiz-Meoz, Daniel Krosky, Christophe Buyck, Carolina Martinez Lamenca, Josep Llaveria, Lichao Fang, Jay H. Kalin, Vincent N. A. Klaren, Shorouk Fahmy, Paul L. Shaffer, Robert Kirkpatrick, Rodrigo J. Carbajo, Maren Thomsen, Antonietta Impagliazzo
Summary: Rational engineering and structural analysis of human spermine oxidase resulted in the determination of its crystal structure and the development of a highly selective allosteric inhibitor, providing important insights for further drug research and development for the treatment of inflammation and cancer.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
K. Dileep, Kentaro Ihara, Chiemi Mishima-Tsumagari, Mutsuko Kukimoto-Niino, Mayumi Yonemochi, Kazuharu Hanada, Mikako Shirouzu, Kam Y. J. Zhang
Summary: Alzheimer's disease is a common neurodegenerative disorder in the elderly population, and impairment of the cholinergic system is a critical factor for its progression. Tacrine, as an AChE inhibitor, is promising for restoring cholinergic transmission. This study reveals the atomic level interactions between tacrine and human AChE, providing a mechanistic explanation for its high binding affinity.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Multidisciplinary Sciences
Ho-Soo Lee, Sunwoo Min, Ye-Eun Jung, Sunyoung Chae, June Heo, Jae-Ho Lee, TaeSoo Kim, Ho-Chul Kang, Makoto Nakanish, Sun-Shin Cha, Hyeseong Cho
Summary: The study reveals that the RSF1-PLK1 axis plays a crucial role in the activation of Aurora B, enhancing its catalytic activity through phosphorylation and promoting chromosome alignment and segregation. This kinase combination is crucial for regulating dynamic microtubule-kinetochore attachment in early mitosis.
NATURE COMMUNICATIONS
(2021)
Article
Virology
Xiaofei Dong, Xue Wang, Mengjia Xie, Wei Wu, Zhongzhou Chen
Summary: Human parainfluenza virus 3 (HPIV3) causes annual epidemics of respiratory diseases, especially in newborns and infants. The core components consist of just three viral proteins: nucleoprotein (N), phosphoprotein (P), and RNA polymerase (L). The study revealed the structure of unassembled HPIV3 N-0 in complex with the N-terminal portion of the P, showing that P mainly binds to the C-terminal domain of N-0 by hydrophobic interaction and interferes with the formation of N-RNA oligomers, which could be a potential target for drug development.
JOURNAL OF VIROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xianghua Zhang, Ji Eun Park, Eun Ho Kim, Jihee Hong, Ki-Tae Hwang, Young A. Kim, Chang-Young Jang
Summary: The timely and temporal phosphorylation of proteins during mitosis is critical, with mitotic kinases activating and phosphatases repressing the process. The mitotic exit, or transition from mitosis to interphase, involves removal of mitotic phosphorylation by protein phosphatases, including PP1 and PP2A. A new mitotic phosphatase relay, involving Wip1/PPM1D phosphatase activity, is essential for CPC translocation in anaphase, demonstrating spatiotemporal regulation of mitotic exit to prevent tumor initiation and progression.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Midori Usami, Koki Ando, Asuka Shibuya, Ryoko Takasawa, Hideshi Yokoyama
Summary: Human glyoxalase I (hGLO I) is an enzyme that detoxifies methylglyoxal (MG) and is a promising target for anticancer drug development. The crystal structures of hGLO I and its complex with the GLO I inhibitor TLSC702 were determined, providing a structural basis for the development of improved anticancer drugs.
Article
Biochemistry & Molecular Biology
M. Rhyan Puno, Christopher D. Lima
Summary: RNA quality control relies on co-factors and adaptors to identify and prepare substrates for degradation. Cryogenic electron microscopy structures of human nuclear exosome targeting complexes reveal mechanistic insights to substrate recognition and early steps before RNA handover. ZCCHC8 serves as a scaffold, mediating homodimerization and facilitating RNA capture by MTR4, while RBM7 anchors to the helicase core. These interactions coordinate RNA capture, translocation, and decay.
Article
Chemistry, Multidisciplinary
Vaclav Nemec, Prashant Khirsariya, Pavlina Janovska, Paula Martin Moyano, Lukas Maier, Petra Prochazkova, Pavlina Kebkova, Tomas Gybel', Benedict-Tilman Berger, Apirat Chaikuad, Maria Reinecke, Bernhard Kuster, Stefan Knapp, Vitezslav Bryja, Kamil Paruch
Summary: In this study, a new class of potent and highly selective inhibitors of CK1 alpha, delta and epsilon were identified. MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms due to their optimal in vitro and in vivo profiles and exclusive selectivity. Furthermore, it was found that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, such as p38 alpha.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Biology
Federica Scotto di Carlo, Sharon Russo, Francesc Muyas, Maria Mangini, Lorenza Garribba, Laura Pazzaglia, Rita Genesio, Flavia Biamonte, Anna Chiara De Luca, Stefano Santaguida, Katia Scotlandi, Isidro Cortes-Ciriano, Fernando Gianfrancesco
Summary: Profilin 1, encoded by PFN1, is a protein that plays a tumor suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its exact contribution to tumor development is not fully understood. This study shows that inactivation of Profilin 1 leads to multiple mitotic defects, resulting in chromosomal instability and genome rearrangements in pagetic osteosarcomas. Mechanistically, Profilin 1 is involved in regulating cell division and its deficiency impairs actin filament supply during cytokinesis.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Mohamed Hasyeoui, Frederic Lassagne, William Erb, Manal Nael, Khaled M. Elokely, Apirat Chaikuad, Stefan Knapp, Adrian Jorda, Soraya L. Vall, Emie Quissac, Maite Verreault, Thomas Robert, Stephane Bach, Ali Samarat, Florence Mongin
Summary: The effects of FL-291 on the viability of neuroblastoma cells were investigated and found to have no significant impact on cell survival. Structural analysis revealed similar binding modes for FL-291 and CD-07 with GSK-3 beta. A library of analogs was designed and synthesized, and the new inhibitor MH-124 exhibited clear selectivity for GSK-3 alpha.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Soumitra Polley, Helen Mueschenborn, Melina Terbeck, Anna De Antoni, Ingrid R. Vetter, Marileen Dogterom, Andrea Musacchio, Vladimir A. Volkov, Pim J. Huis In 't Veld
Summary: During cell division, the Ndc80 complex plays a crucial role in linking chromosomes to spindle microtubules. This study demonstrates that the Ndc80 loop promotes direct interactions between adjacent Ndc80 complexes, which are necessary for stable end-on kinetochore-microtubule attachment and spindle assembly checkpoint satisfaction. Mutations in the loop impair these interactions and lead to cell arrest in mitosis.
Article
Chemistry, Medicinal
Rohit Arora, Joannes T. M. Linders, Samia Aci-Seche, Thomas Verheyen, Erika Van Heerde, Dirk Brehmer, Apirat Chaikuad, Stefan Knapp, Pascal Bonnet
Summary: The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors efficiently block the MAPK pathways in B-Raf mutant cells but induce conformational changes in the wild type B-Raf (wtB-Raf) kinase domain causing paradoxical hyperactivation. Type II inhibitors prevent heterodimerization by binding the kinase in the DFG-out conformation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Marcel Rak, Roberta Tesch, Lena M. Berger, Ekaterina Shevchenko, Monika Raab, Amelie Tjaden, Rezart Zhubi, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Antti Poso, Andreas Kra, Lewis Elson, Aleksandar Luc, Thales Kronenberger, Thomas Hanke, Klaus Strebhardt, Mourad Sanhaji, Stefan Knapp
Summary: Salt-inducible kinases 1-3 (SIK1-3) are important regulators of cellular homeostasis. This study presents a structure-based approach to improve the selectivity of inhibitors targeting SIK kinases, resulting in the development of a valuable tool compound, MR22, which showed excellent selectivity and phenotypic effects in ovarian cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Han Wee Ong, Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael Chirgwin, Kareem A. Galal, Caleb Willis, Andreas Kramer, Shubin Liu, Stefan Knapp, Emily R. Derbyshire, Reena Zutshi, David H. Drewry
Summary: Malaria is a global health problem with high morbidity and mortality rates. The emergence of drug resistance against current treatments emphasizes the need for alternative antimalarials. In this study, we discovered Ki8751 as an inhibitor of essential kinase PfPK6 and identified two compounds (67 and 79) with potent antiplasmodial activity against both blood and liver stages of malaria.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Maria Mushtaq Ali, Sehrish Naz, Sajda Ashraf, Stefan Knapp, Zaheer Ul-Haq
Summary: BRD9 inhibitors have potential therapeutic value in cancer treatment by selectively targeting BRD9 and BRD7 proteins, regulating chromatin structure and gene expression, and inhibiting tumor growth and progression.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Martin P. Schwalm, Stefan Knapp, Vladimir V. Rogov
Summary: Induction of LC3/GABARAP protein interactions with target proteins by small molecules has the potential for targeted protein degradation, but no potent ligands have been developed despite intensive screening campaigns in the past 5 years, limiting its therapeutic applications.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jun Yong Choi, Yoshihiko Noguchi, James M. Alburger, Simon Bayle, Eugene Chung, Wayne Grant, Apirat Chaikuad, Stefan Knapp, Derek R. Duckett, William R. Roush
Summary: Inhibiting a single kinase isoform is difficult due to the similarity of ATP-binding sites. Through studying crystal structures, a highly selective inhibitor for CK1 & epsilon; (SR-4133) was developed. The mismatch between SR-4133 and CK1 & delta; destabilizes their interaction, while the hydrophobic surface of CK1 & epsilon; enhances the binding of SR-4133, leading to selective inhibition. These potent CK1 & epsilon;-selective inhibitors exhibit nanomolar growth inhibition in bladder cancer cells and inhibit the phosphorylation of 4E-BP1, a downstream effector of CK1 & epsilon;.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Emmanuel Deau, Mattias F. F. Lindberg, Freideiric Miege, Didier Roche, Nicolas George, Pascal George, Andreas Kra''mer, Stefan Knapp, Laurent Meijer
Summary: Dual-specificity,tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) have been identified as important targets for various pathologies. In this study, a family of DYRK/CLK inhibitors called Leucettinibs, derived from Leucettines and Leucettamine B, were synthesized and characterized. These inhibitors showed subnanomolar IC50 on DYRK1A and demonstrated potential for therapeutic drug development. Kinase-inactive isomers, iso-Leucettinibs, were also synthesized as suitable negative control compounds. Leucettinibs were found to inhibit DYRK1A substrate phosphorylation in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Silvia Arifi, Julian A. Marschner, Julius Pollinger, Laura Isigkeit, Pascal Heitel, Astrid Kaiser, Lennart Obeser, Georg Hoefner, Ewgenij Proschak, Stefan Knapp, Apirat Chaikuad, Jan Heering, Daniel Merk
Summary: The lipid-sensing transcription factor PPAR γ can bind to antidiabetic TZD drugs, oxidized vitamin E metabolites, and vitamin E mimetic garcinoic acid. While the effects of the second binding on PPAR γ activity are unclear, a selective ligand of the second site has been developed, revealing potential noncanonical regulation of PPAR γ activities. This alternative binding diminishes FOXO signaling and may have therapeutic applications.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Cell Biology
Chanchal Chauhan, Andreas Kraemer, Stefan Knapp, Mark Windheim, Alexey Kotlyarov, Manoj B. Menon, Matthias Gaestel
Summary: This study investigates the role of MAPK-activated protein kinase 2 (MK2) in cell death and identifies 5-Iodotubercidin (5-ITu) as a potent compound that sensitizes MK2-deficient cells to TNF-induced death. It is found that 5-ITu induces RIPK1-dependent necroptosis by suppressing IKK signaling in the absence of MK2 activity.
CELL DEATH DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Martin P. Schwalm, Andreas Kraemer, Anja Doelle, Janik Weckesser, Xufen Yu, Jian Jin, Krishna Saxena, Stefan Knapp
Summary: Cell-based assays using NanoLuciferase and HaloTag were developed to measure the kinetics and stability of PROTAC-induced degradation and ternary complex formation. Characterization of PROTACs targeting WDR5 revealed the importance of ternary complex formation and stability in the early degradation cascade. Comparison of ternary complex crystal structures highlighted the significance of an efficient E3-target interface for ternary complex stability. This study provides a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC-induced degradation pathway.
CELL CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Verena Cmentowski, Giuseppe Ciossani, Ennio d'Amico, Sabine Wohlgemuth, Mikito Owa, Brian Dynlacht, Andrea Musacchio
Summary: The RZZS complex and CENP-E are closely connected and reciprocally required for their own kinetochore recruitment and dynein localization to the corona.
