Review
Oncology
Motahareh Mortazavi, Fatemeh Moosavi, Miriam Martini, Elisa Giovannetti, Omidreza Firuzi
Summary: This study highlights the role of PI3K/AKT/mTOR pathway in pancreatic ductal adenocarcinoma, but clinical studies have not been promising. Patient stratification is identified as a crucial factor.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2022)
Article
Cell Biology
Song Han, Peng-Fei Wang, Hong-Qing Cai, Jing-Hai Wan, Shou-Wei Li, Ze-Huan Lin, Chun-Jiang Yu, Chang-Xiang Yan
Summary: The study reveals a strong correlation between altered RTK/Ras/PI3K/AKT signaling and immunotherapy biomarkers in gliomas, suggesting that gliomas with changes in these pathways may be sensitive to immunotherapy. Combined treatment with small-molecule kinase inhibitors and immunotherapy is proposed for this subgroup of tumors with altered RTK/Ras/PI3K/AKT pathways.
Article
Cell Biology
Martina Tufano, Laura Marrone, Chiara D'Ambrosio, Valeria Di Giacomo, Simona Urzini, Yichuan Xiao, Monica Matuozzo, Andrea Scaloni, Maria Fiammetta Romano, Simona Romano
Summary: FKBP51 is crucial for the survival of cancer cells, especially melanoma. It involved in various signaling pathways and forms a complex with Akt and PHLPP, known for dephosphorylation of Akt. This study focuses on the regulation of Akt activation by canonical and spliced isoforms of FKBP51. The TPR domain of FKBP51 is found to mediate Akt ubiquitination at K63, an important step for Akt activation. Surprisingly, PHLPP does not promote Akt phosphorylation when silenced and even induces Akt phosphorylation when overexpressed. PHLPP stabilizes TRAF6, an E3 ubiquitin ligase, and supports K63-ubiquitination of Akt. The interactome profile of FKBP51 in melanoma cells emphasizes the crucial role of PHLPP in enhancing oncogenic characteristics, particularly cell proliferation.
CELL DEATH & DISEASE
(2023)
Article
Chemistry, Medicinal
Leandi Westhuizen, Joern Weisner, Abu Taher, Ina Landel, Lena Quambusch, Marius Lindemann, Niklas Uhlenbrock, Matthias P. Mueller, Ivan R. Green, Stephen C. Pelly, Daniel Rauh, Willem A. L. van Otterlo
Summary: This study designed a small library of potential covalent allosteric imidazopyridine-based inhibitors and explored their binding modes, potencies, and antiproliferative activities. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines.
Article
Chemistry, Multidisciplinary
Wei Xiong, Bin Zhang, Haixin Yu, Liang Zhu, Lu Yi, Xin Jin
Summary: The study reveals that upregulated RRM2 in sunitinib-resistant RCC promotes resistance to TKIs, but the exact mechanism remains unclear. Additionally, RRM2 also impacts anti-tumor immune responses, and silencing RRM2 can enhance the efficacy of PD-1 blockade in renal cancer.
Review
Biochemistry & Molecular Biology
Antonino Glaviano, Aaron S. C. Foo, Hiu Y. Lam, Kenneth C. H. Yap, William Jacot, Robert H. Jones, Huiyan Eng, Madhumathy G. Nair, Pooyan Makvandi, Birgit Geoerger, Matthew H. Kulke, Richard D. Baird, Jyothi S. Prabhu, Daniela Carbone, Camilla Pecoraro, Daniel B. L. Teh, Gautam Sethi, Vincenzo Cavalieri, Kevin H. Lin, Nathalie R. Javidi-Sharifi, Eneda Toska, Matthew S. Davids, Jennifer R. Brown, Patrizia Diana, Justin Stebbing, David A. Fruman, Alan P. Kumar
Summary: The PI3K/AKT/mTOR (PAM) signaling pathway plays a crucial role in cell survival, growth, and cell cycle progression. Dysregulation of this pathway is associated with cancer development and resistance to therapy. This review focuses on the major dysregulations in the PAM signaling pathway in cancer and discusses strategies for overcoming treatment resistance. The role of PAM signaling in immunology and immunotherapies is also discussed.
Article
Oncology
Yan Sun, Liang Zhu, Pian Liu, Huan Zhang, Feng Guo, Xin Jin
Summary: In this study, researchers found that the upregulation of palmitoyl acyltransferase ZDHHC2 is associated with TKI resistance in ccRCC. ZDHHC2 mediates AGK S-palmitoylation to activate the PI3K-AKT-mTOR signaling pathway, which modulates sunitinib sensitivity. These findings suggest that targeting ZDHHC2 may improve the efficacy of sunitinib in treating ccRCC.
Article
Oncology
Aurimas Stulpinas, Matas Sereika, Aida Vitkeviciene, Ausra Imbrasaite, Natalija Krestnikova, Audrone V. V. Kalvelyte
Summary: Cell signaling manipulation is crucial for anticancer therapy, and the cell state determines the response to drugs. Therefore, understanding the relationship between cell state and therapeutic sensitivity is essential for the development of cancer treatments. Patient-derived ex vivo cell models show promise in translating research findings into clinical applications in the era of personalized medicine.
FRONTIERS IN ONCOLOGY
(2023)
Article
Chemistry, Medicinal
Deborah S. Mortensen, Sayee G. Hegde, Sophie M. Perrin-Ninkovic, Sogole Bahmanyar, Meg McCarrick, Roy Harris, Robert Hilgraf, Branden G. S. Lee, Jeff McKie, Lisa Nadolny, John Sapienza, Alice Collette, Sarah Cox, James C. Gamez, Jennifer L. Hensel, Xuequn Helen Hua, Jim Leisten, Heather K. Raymon, Tam Tran, Rama Krishna Narla
Summary: We have discovered and optimized a novel series of AKT kinase inhibitors, guided by the structure of the target protein. Docking studies led to the development of a potent series of N-substituted-5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-amines. These compounds inhibit the AKT pathway in cancer cells by suppressing the phosphorylation of pathway proteins pGSK and pFKHR. In vivo studies using compound 12 showed inhibition of phosphorylation of the direct substrate GSK and pathway biomarker S6 in tumor-bearing mice.
MEDICINAL CHEMISTRY RESEARCH
(2023)
Review
Oncology
Wojciech Wiese, Julia Barczuk, Olga Racinska, Natalia Siwecka, Wioletta Rozpedek-Kaminska, Artur Slupianek, Radoslaw Sierpinski, Ireneusz Majsterek
Summary: The PI3K/Akt/mTOR pathway is crucial in cancer development and can be a potential therapeutic target for leukemia. Recent research indicates that inhibition of this pathway may lead to improved treatment outcomes for leukemia.
Article
Cell Biology
Hao Wang, Wei Hou, Aldeb Perera, Carlee Bettler, Jordan R. Beach, Xianzhong Ding, Jun Li, Mitchell F. Denning, Asha Dhanarajan, Scott J. Cotler, Cara Joyce, Jun Yin, Fowsiyo Ahmed, Lewis R. Roberts, Wei Qiu
Summary: EphA2 expression is enriched in human HCC and loss of EphA2 can suppress the initiation and growth of HCC. Targeting EphA2 inhibits both AKT and JAK1/STAT3 signaling pathways in HCC, and a small molecule kinase inhibitor of EphA2 shows promising results in suppressing tumor progression in a murine model.
Article
Polymer Science
Tahir Mehmood, Rath Pichyangkura, Chatchai Muanprasat
Summary: This study demonstrates that chitosan oligosaccharide can reduce the diarrhea induced by afatinib and regulate the tight junctions and chloride secretion in intestinal epithelial cells by activating AMPK. This study provides a promising natural polymer-derived compound for further development of treatment for afatinib-associated diarrhea.
Article
Biology
Marina Cerqua, Orsola Botti, Maddalena Arigoni, Noemi Gioelli, Guido Serini, Raffaele Calogero, Carla Boccaccio, Paolo M. Comoglio, Dogus M. Altintas
Summary: MET is an oncogene that encodes a tyrosine kinase receptor for hepatocyte growth factor (HGF). When MET is mutated or amplified, it becomes a driver for cancer. The most common mutation in the MET gene affects the splicing sites of exon 14, leading to the deletion of a receptor domain. Our analysis showed that MET Delta 14 is dependent on HGF for kinase activation and has enhanced cellular protection and migration.
LIFE SCIENCE ALLIANCE
(2022)
Article
Multidisciplinary Sciences
Kelsie J. Anson, Giulia A. Corbet, Amy E. Palmer
Summary: In this study, the researchers investigated how changes in intracellular zinc ion levels affect kinase signaling pathways using fluorescent biosensors and cell perturbations. The results showed that zinc ion fluctuations are not toxic and do not activate stress-dependent kinase signaling. Additionally, the study demonstrated that while zinc ions can inhibit phosphatases, ERK and Akt are primarily activated through upstream signaling pathways.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Pharmacology & Pharmacy
Alan Umfress, Sarbjit Singh, Kevin J. Ryan, Ayanabha Chakraborti, Florian Plattner, Yogesh Sonawane, Jayapal Reddy Mallareddy, Edward P. Acosta, Amarnath Natarajan, James A. Bibb
Summary: Cyclin-dependent kinase 5 (Cdk5) is a crucial regulator of neuronal signal transduction and its activity is implicated in various neuropsychiatric and neurodegenerative conditions. In this study, a novel brain-penetrant Cdk5 inhibitor 25-106 was identified, which showed promising effects on behavior and has significant potential as a neurological/neuropsychiatric therapeutic.
FRONTIERS IN PHARMACOLOGY
(2022)
Meeting Abstract
Oncology
Xiaoyan Wang, Amy Farrell, Mahnaz Janghorban, Brittany Allen-Petersen, Juan Liang, Tyler Risom, Michael Ohlmeyer, Goutham Narla, Rosalie C. Sears
Article
Chemistry, Medicinal
Steve Wenglowsky, Li Ren, Jonas Grina, Joshua D. Hansen, Ellen R. Laird, David Moreno, Victoria Dinkel, Susan L. Gloor, Gregg Hastings, Sumeet Rana, Kevin Rasor, Hillary L. Sturgis, Walter C. Voegtli, Guy Vigers, Brandon Willis, Simon Mathieu, Joachim Rudolph
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Chemistry, Medicinal
Matthew Volgraf, Lina Chan, Malcolm P. Huestis, Hans E. Purkey, Michael Burkard, Mary Geck Do, Julie Harris, Kevin W. Hunt, Xingrong Liu, Joseph P. Lyssikatos, Sumeet Rana, Allen A. Thomas, Guy P. A. Vigers, Michael Siu
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2014)
Meeting Abstract
Oncology
Tyler Risom, Juha Rantala, Ellen Langer, Nicholas Wang, Laura Heiser, Megan Troxell, Joe Gray, Rosalie Sears
Article
Chemistry, Medicinal
Yutong Jiang, Steven W. Andrews, Kevin R. Condroski, Brad Buckman, Vlad Serebryany, Steve Wenglowsky, April L. Kennedy, Machender R. Madduru, Bin Wang, Michael Lyon, George A. Doherty, Benjamin T. Woodard, Christine Lemieux, Mary Geck Do, Hailong Zhang, Joshua Ballard, Guy Vigers, Barbra J. Brandhuber, Peter Stengel, John A. Josey, Leonid Beigelman, Lawrence Blatt, Scott D. Seiwert
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Chemistry, Medicinal
Allen A. Thomas, Kevin W. Hunt, Matthew Volgraf, Ryan J. Watts, Xingrong Liu, Guy Vigers, Darin Smith, Douglas Sammond, Tony P. Tang, Susan P. Rhodes, Andrew T. Metcalf, Karin D. Brown, Jennifer N. Otten, Michael Burkard, April A. Cox, Mary K. Geck Do, Darrin Dutcher, Sumeet Rana, Robert K. DeLisle, Kelly Regal, Albion D. Wright, Robert Groneberg, Kimberly Scearce-Levie, Michael Siu, Hans E. Purkey, Joseph P. Lyssikatos, Indrani W. Gunawardana
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Chemistry, Medicinal
Allen A. Thomas, Kevin W. Hunt, Brad Newhouse, Ryan J. Watts, Xingrong Liu, Guy Vigers, Darin Smith, Susan P. Rhodes, Karin D. Brown, Jennifer N. Otten, Michael Burkard, April A. Cox, Mary K. Geck Do, Darrin Dutcher, Sumeet Rana, Robert K. DeLisle, Kelly Regal, Albion D. Wright, Robert Groneberg, Jiangpeng Liao, Kimberly Scearce-Levie, Michael Siu, Hans E. Purkey, Joseph P. Lyssikatos
JOURNAL OF MEDICINAL CHEMISTRY
(2014)
Article
Multidisciplinary Sciences
Tyler Risom, Ellen M. Langer, Margaret P. Chapman, Juha Rantala, Andrew J. Fields, Christopher Boniface, Mariano J. Alvarez, Nicholas D. Kendsersky, Carl R. Pelz, Katherine Johnson-Camacho, Lacey E. Dobrolecki, Koei Chin, Anil J. Aswani, Nicholas J. Wang, Andrea Califano, Michael T. Lewis, Claire J. Tomlin, Paul T. Spellman, Andrew Adey, Joe W. Gray, Rosalie C. Sears
NATURE COMMUNICATIONS
(2018)
Article
Oncology
Brittany L. Allen-Petersen, Tyler Risom, Zipei Feng, Zhiping Wang, Mary C. Thoma, Katherine R. Pelz, Jennifer P. Morton, Owen J. Sansom, Charles D. Lopez, Brett Sheppard, Dale J. Christensen, Michael Ohlmeyer, Goutham Narla, Rosalie C. Sears
Article
Chemistry, Medicinal
Jay B. Fell, John P. Fischer, Brian R. Baer, Joshua Ballard, James F. Blake, Karyn Bouhana, Barbara J. Brandhuber, David M. Briere, Laurence E. Burgess, Michael R. Burkard, Harrah Chiang, Mark J. Chicarelli, Kevin Davidson, John J. Gaudino, Jill Hallin, Lauren Hanson, Kenneth Hee, Erik J. Hicken, Ronald J. Hinklin, Matthew A. Marx, Macedonio J. Mejia, Peter Olson, Pavel Savechenkov, Niranjan Sudhakar, Tony P. Tang, Guy P. Vigers, Henry Zecca, James G. Christensen
ACS MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Biochemical Research Methods
Margaret P. Chapman, Tyler Risom, Anil J. Aswani, Ellen M. Langer, Rosalie C. Sears, Claire J. Tomlin
PLOS COMPUTATIONAL BIOLOGY
(2019)
Article
Multidisciplinary Sciences
Laurel M. Pegram, Jennifer C. Liddle, Yao Xiao, Maria Hoh, Johannes Rudolph, Dylan B. Iverson, Guy P. Vigers, Darin Smith, Hailong Zhang, Weiru Wang, John G. Moffat, Natalie G. Ahn
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Medicine, Research & Experimental
Tyler Risom, Xiaoyan Wang, Juan Liang, Xiaoli Zhang, Carl Pelz, Lydia G. Campbell, Jenny Eng, Koei Chin, Caroline Farrington, Goutham Narla, Ellen M. Langer, Xiao-Xin Sun, Yulong Su, Colin J. Daniel, Mu-Shui Dai, Christiane V. Lohr, Rosalie C. Sears
JOURNAL OF CLINICAL INVESTIGATION
(2020)
Article
Multidisciplinary Sciences
Leeat Keren, Marc Bosse, Steve Thompson, Tyler Risom, Kausalia Vijayaragavan, Erin McCaffrey, Diana Marquez, Roshan Angoshtari, Noah F. Greenwald, Harris Fienberg, Jennifer Wang, Neeraja Kambham, David Kirkwood, Garry Nolan, Thomas J. Montine, Stephen J. Galli, Robert West, Sean C. Bendall, Michael Angelo
Proceedings Paper
Automation & Control Systems
Margaret P. Chapman, Tyler T. Risom, Anil Aswani, Roel Dobbe, Rosalie C. Sears, Claire J. Tomlin
2016 IEEE 55TH CONFERENCE ON DECISION AND CONTROL (CDC)
(2016)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
