Editorial Material
Cell Biology
Michael J. Munson, Benan J. Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R. de la Ballina, Anne Simonsen
Summary: Maintenance of cellular homeostasis requires the removal of mitochondria through programmed or stress-induced mitophagy. While stress-induced mitophagy is regulated by PRKN, the mechanisms regulating basal mitophagy levels are still poorly understood. Recent research has identified two kinases, GAK and PRKCD, as positive regulators of PRKN-independent mitophagy. PRKCD is found to be localized to mitochondria and regulates the recruitment of ULK1-ATG13 during mitophagy induction. On the other hand, GAK activity modifies mitochondrial and lysosomal morphology, compromising efficient transport of mitochondria for degradation. Impairment of either kinase in vivo blocks basal mitophagy, underscoring the biological significance of these findings.
Article
Neurosciences
Jun Egawa, Reza K. Arta, Vance P. Lemmon, Melissa Munos-Barrero, Yan Shi, Michihiro Igarashi, Toshiyuki Someya
Summary: Protein kinases play important roles in neuronal development, and poorly characterized kinases may also be involved. This study suggests that cyclin G-associated kinase (GAK) may regulate neurite outgrowth and synaptogenesis, and decreased GAK function could lead to impaired neuronal development.
Article
Chemistry, Medicinal
Donghui Huo, Shiyu Wang, Yue Kong, Zijian Qin, Aixia Yan
Summary: The study utilized a ligand-based virtual screening protocol to search for novel EGFR inhibitors from a large compound library, resulting in the establishment of four SAR models and three QSAR models to further screen for highly active EGFR inhibitors. Experimental validation confirmed the activity of nine compounds out of which three had IC50 values around 80 nM against EGFR, with interactions with EGFR explored through molecular dynamics simulations.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Medicine, Research & Experimental
Masaya Miyazaki, Masaki Hiramoto, Naoharu Takano, Hiroko Kokuba, Jun Takemura, Mayumi Tokuhisa, Hirotsugu Hino, Hiromi Kazama, Keisuke Miyazawa
Summary: The study revealed that GAK plays a crucial role in controlling lysosomal dynamics through actomyosin regulation, thereby promoting a steady progression of autophagy. Genetic disruption or chemical inhibition of GAK resulted in impaired autophagosome-lysosome fusion and affected the maintenance of lysosomal homeostasis during autophagy. The findings highlight the importance of GAK in regulating lysosomal dynamics in the autophagy-lysosome system.
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
(2021)
Article
Chemistry, Medicinal
David H. Drewry, Frances M. Potjewyd, Armin Bayati, Jeffery L. Smith, Rebekah J. Dickmander, Stefanie Howell, Sharon Taft-Benz, Sophia M. Min, Mohammad Anwar Hossain, Mark Heise, Peter S. McPherson, Nathaniel J. Moorman, Alison D. Axtman
Summary: A highly potent and cell-active chemical probe (17) that inhibits PIKfyve with excellent selectivity has been identified from a designed library of indolyl pyrimidinamines. This probe disrupts multiple phases of the lifecycle of beta-coronaviruses.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
David H. Drewry, Frances M. Potjewyd, Armin Bayati, Jeffery L. Smith, Rebekah J. Dickmander, Stefanie Howell, Sharon Taft-Benz, Sophia M. Min, Mohammad Anwar Hossain, Mark Heise, Peter S. McPherson, Nathaniel J. Moorman, Alison D. Axtman
Summary: A highly potent and cell-active chemical probe was identified from a designed library of indolyl pyrimidinamines, which inhibits phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). This PIKfyve probe disrupts multiple phases of the lifecycle of beta-coronaviruses and demonstrates excellent kinome-wide selectivity, making it a valuable tool for further characterization of the role of PIKfyve in virology.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Plant Sciences
Rui-Yi Yang, Jia-Yi Tan, Zhe Liu, Xiao-Ling Shen, Ying-Jie Hu
Summary: The natural lignan LAF from Arctium lappa Linne has been found to inhibit tumor cell growth in vitro and in vivo. However, its role in cell cycle regulation remains unknown.
PHARMACEUTICAL BIOLOGY
(2023)
Article
Oncology
Jing Hang, Hanqiang Ouyang, Feng Wei, Qihang Zhong, Wanqiong Yuan, Liang Jiang, Zhongjun Liu
Summary: In this study, we comprehensively analyzed the protein and phosphoprotein profiles of chordoma using proteomic and phosphoproteomic approaches. We identified aberrant expression of proteins and phosphorylation events in chordoma tumor tissues, and predicted the involvement of key kinases in the development of chordoma. We also demonstrated the therapeutic potential of targeting these kinases in inhibiting chordoma cell growth.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Medicinal
Belen Martinez-Gualda, Sirle Saul, Mathy Froeyen, Dominique Schols, Piet Herdewijn, Shirit Einav, Steven De Jonghe
Summary: Inserting a carboxamide residue at position 3 of the scaffold can generate potent GAK inhibitors with antiviral activity against dengue virus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, General & Internal
Wen-Ru Chou, Ben-Chang Shia, Yen-Chun Huang, Chieh-Wen Ho, Mingchih Chen
Summary: This study, based on Taiwan's National Health Insurance Research Database (NHIRD), aimed to investigate the risk factors for second primary cancers (SPCs) in lung cancer survivors and the impact of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment on the development of SPCs.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Pharmacology & Pharmacy
Yazan Haddad, Marek Remes, Vojtech Adam, Zbynek Heger
Summary: The study utilized variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. These families shared similar mutational profiles, ligand R-groups facing the C-helix, mutation sites, and DFG domain.
DRUG DISCOVERY TODAY
(2021)
Article
Cell Biology
Kanta Yamazoe, Yoshihiro H. Inoue
Summary: The Cdk1-CycB complex is crucial for cell-cycle regulation. Import and export processes are important for the localization and activation of Cdk1. Interaction between Cdc25C and Cdk-activating kinase with Cdk1 in the nucleus is necessary for centrosome separation.
Article
Oncology
Elena Garralda, Alison M. Schram, Philippe L. Bedard, Gary K. Schwartz, Eunice Yuen, Samuel C. McNeely, Silvia Ribeiro, Jason Cunningham, Yi Wang, Arantxa Urunuela, Xiaojian Xu, Patricia LoRusso
Summary: LY3405105 is a promising CDK7 inhibitor with good bioavailability and selectivity. However, the clinical trial showed limited efficacy and no plans for further development. The MTD of LY3405105 monotherapy was determined to be 20 mg QD.
Article
Oncology
Kenichi Inoue, Norikazu Masuda, Hiroji Iwata, Masato Takahashi, Yoshinori Ito, Yasuo Miyoshi, Takahiro Nakayama, Hirofumi Mukai, Jan-Stefan van der Walt, Joji Mori, Sachi Sakaguchi, Tsutomu Kawaguchi, Yoshinori Tanizawa, Antonio Llombart-Cussac, George W. Sledge, Masakazu Toi
Summary: In the Japanese subpopulation analysis of the MONARCH 2 study, abemaciclib plus fulvestrant demonstrated significantly prolonged progression-free survival, higher objective response rate, and good safety profile in treating advanced breast cancer patients. Results were consistent with those of the overall population.
Editorial Material
Chemistry, Medicinal
Mark Klein
Summary: Cyclin-dependent kinases (CDKs) have important roles in normal cells and can be targeted for cancer therapy. CDK4 inhibitors have been approved for advanced breast cancer treatment. However, the development of selective inhibitors for individual CDKs is challenging due to the highly conserved ATP-binding site.
Article
Chemistry, Medicinal
David H. Drewry, Joel K. Annor-Gyamfi, Carrow Wells, Julie E. Pickett, Verena Dederer, Franziska Preuss, Sebastian Mathea, Alison D. Axtman
Summary: The pyrimidine core has been widely used in constructing kinase inhibitors, and the strategy of utilizing nonexemplified aminopyrimidines with side chains from annotated inhibitors has provided useful inhibitors for understudied kinases. By mixing and matching side chains from parent compounds and modifying the 5-position of the pyrimidine core, improved kinome-wide selectivity was achieved. Important lead compounds for understudied kinases such as DRAK1, BMP2K, and MARK3/4 were also identified through this approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Candice J. Crilly, Julia A. Brom, Owen Warmuth, Harrison J. Esterly, Gary J. Pielak
Summary: The study found that intrinsically disordered proteins (IDPs) provide better protection against dehydration-induced unfolding, mainly through electrostatic interactions formed by charge patterning and expanded conformations to protect the client proteins. These findings will help deepen our understanding of dehydration protection mechanisms and streamline the production of dehydrated proteins for expanded use in the medical, biotechnology, and chemical industries.
Article
Multidisciplinary Sciences
Timothy J. Fazekas, Jill W. Alty, Eliza K. Neidhart, Austin S. Miller, Frank A. Leibfarth, Erik J. Alexanian
Summary: This study reports an approach to achieve diverse functionality on hydrocarbons by utilizing radical chain transfer. By using an easily prepared reagent, a range of functionalizations on small molecules and polyolefins can be achieved. This method has also been applied in the processing of plastic waste and enables the introduction of ionic functionality on polyolefins, transforming them into elastomers with high-value properties.
Article
Chemistry, Medicinal
Christopher R. M. Asquith, Louisa Temme, Michael P. East, Tuomo Laitinen, Julie Pickett, Frank E. Kwarcinski, Parvathi Sinha, Carrow Wells, Gary L. Johnson, Reena Zutshi, David H. Drewry
Summary: Compound 16 was identified as a potent inhibitor of Protein Kinase Novel 3 (PKN3) with micromolar activity in cells. It has the potential to serve as a tool compound for studying the cell biology of PKN3 and its role in pancreatic and prostate cancer and T-cell acute lymphoblastic leukemia.
Article
Cell Biology
Carrow Wells, Yi Liang, Thomas L. Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M. Counago, Brittany Stork, Christopher G. Langendorf, Kevin Nay, Jonathan S. Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R. Means, Brian York, Donald P. McDonnell, John W. Scott, Daniel E. Frigo, David H. Drewry
Summary: This study presents a selective small molecule probe, SGC-CAMKK2-1, that specifically targets CAMKK2, which can be used to investigate the therapeutic benefits of CAMKK2 inhibition.
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
Thaila Fernanda dos Reis, Patricia Alves de Castro, Rafael Wesley Bastos, Camila Figueiredo Pinzan, Pedro F. N. Souza, Suzanne Ackloo, Mohammad Anwar Hossain, David Harold Drewry, Sondus Alkhazraji, Ashraf S. Ibrahim, Hyunil Jo, Jorge D. Lightfoot, Emily M. Adams, Kevin K. Fuller, William F. deGrado, Gustavo H. Goldman
Summary: This study demonstrates the synergistic activity of the host defense peptide mimetic brilacidin with caspofungin against various fungal strains, including those that are resistant to caspofungin. These findings suggest that the combination of brilacidin with antifungal drugs currently in clinical use can improve the treatment outcome of aspergillosis and other fungal infections.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Frances M. M. Bashore, Ariana B. B. Marquez, Apirat Chaikuad, Stefanie Howell, Andrea S. S. Dunn, Alvaro A. A. Beltran, Jeffery L. L. Smith, David H. H. Drewry, Adriana S. S. Beltran, Alison D. D. Axtman
Summary: Tau tubulin kinase 1 and 2 (TTBK1/2) are highly homologous kinases that play important roles in brain-related pathways. TTBK1 is involved in diseases like Alzheimer's disease and amyotrophic lateral sclerosis, while TTBK2 is critical for cilia assembly. In this study, a targeted library was designed to identify chemical tools that can inhibit TTBK1 and TTBK2 and affect downstream signaling. Compound 10 was found to significantly reduce primary cilia expression in human induced pluripotent stem cells (iPSCs), confirming the role of TTBK2 in ciliogenesis.
SCIENTIFIC REPORTS
(2023)
Review
Oncology
Khoa Nguyen, Julia Boehling, Minh N. Tran, Thomas Cheng, Andrew Rivera, Bridgette M. Collins-Burow, Sean B. Lee, David H. Drewry, Matthew E. Burow
Summary: Kinases are biomolecules essential for cellular reactions, but disruptions in their expression and activity can lead to diseases like cancer. Though significant progress has been made, a large portion of the human kinome remains understudied. This review focuses on the understudied NEK family of kinases, discussing existing studies, gene expression correlations with patient survival, NEK mutations in different cancer tissues, and potential funding opportunities.
Article
Oncology
Jiung Nam, Amelia U. Schirmer, Chelsea Loh, David H. Drewry, Everardo Macias
Summary: Breast cancer is the most common type of cancer in women, and its treatment is often associated with cardiovascular toxicity. This study explores the potential of targeting the protein kinase STK3 in breast cancer therapy and cardioprotection. STK3 is amplified in breast cancer and is associated with worse patient outcomes, suggesting a noncanonical pro-tumorigenic role. Different breast cancer cell lines have varying dependence on STK3, and its inhibition has shown therapeutic effects in suppressing cancer growth and protecting cardiomyocytes from the toxic effects of chemotherapy. STK3 inhibition does not interfere with the therapeutic efficacy of doxorubicin. This research highlights the potential of STK3 as a molecular target for breast cancer treatment, offering dual therapeutic effects.
Article
Chemistry, Medicinal
Ricardo D. Gonzalez, George W. Small, Adrian J. Green, Farida S. Akhtari, Alison A. Motsinger-Reif, Julia C. F. Quintanilha, Tammy M. Havener, David M. Reif, Howard L. McLeod, Tim Wiltshire
Summary: A genetic variant in the lncRNA gene MKX-AS1 and its paired sense gene MKX could impact the response of cell lines to oxaliplatin treatment. Patients with high MKX-AS1 expression had worse overall survival, while those with high MKX expression had better overall survival. This suggests that MKX-AS1 and MKX expression status could be useful as prognostic markers in colorectal cancer treatment.
Review
Biochemistry & Molecular Biology
Brian Anderson, Peter Rosston, Han Wee Ong, Mohammad Anwar Hossain, Zachary W. Davis-Gilbert, David H. Drewry
Summary: This article analyzes data on human kinases, including citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. The analysis reveals that many kinases are understudied and there is untapped potential for further development. The article also discusses different strategies for generating selectivity between kinases. In conclusion, the authors believe it is possible to develop a tool compound for every human kinase.
BIOCHEMICAL JOURNAL
(2023)
Article
Chemistry, Medicinal
David H. Drewry, Frances M. Potjewyd, Armin Bayati, Jeffery L. Smith, Rebekah J. Dickmander, Stefanie Howell, Sharon Taft-Benz, Sophia M. Min, Mohammad Anwar Hossain, Mark Heise, Peter S. McPherson, Nathaniel J. Moorman, Alison D. Axtman
Summary: A highly potent and cell-active chemical probe (17) that inhibits PIKfyve with excellent selectivity has been identified from a designed library of indolyl pyrimidinamines. This probe disrupts multiple phases of the lifecycle of beta-coronaviruses.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Kareem A. Galal, Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael E. Chirgwin, Eric Merten, Han Wee Ong, Caleb Willis, Ahmad Abdelwaly, Mohamed A. Helal, Emily R. Derbyshire, Reena Zutshi, David H. Drewry
Summary: In this study, a dual PfGSK3/PfPK6 inhibitor IKK16 was discovered to be active against blood stage Pf3D7 parasites, and dual PfGSK3/PfPK6 inhibitors 23d and 23e with antiplasmodial activity were identified. However, these inhibitors exhibited promiscuity in human kinase targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
