Article
Chemistry, Physical
Zhiwei Ma, Sheng-You Huang, Fei Cheng, Xiaoqin Zou
Summary: Efficient ensemble docking algorithm is applied to dock ligands against multiple protein targets simultaneously. Using protein kinases as an example, the algorithm is shown to be effective in screening for inhibitors and investigating their selectivities for multiple target proteins.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Cell Biology
You-Liang Lai, Kai-Hung Wang, Hsing-Pang Hsieh, Wan-Ching Yen
Summary: DBPR114 showed activity against HCC tumor cell proliferation in vitro regardless of p53 alteration status and tumor grade. It induced growth inhibition in HCC cells through apoptosis induction, cell cycle arrest, and polyploidy formation. DBPR114 also exhibited anti-angiogenic effects and significantly inhibited tumor growth in multiple HCC tumor xenograft models.
JOURNAL OF BIOMEDICAL SCIENCE
(2022)
Article
Chemistry, Organic
Atul Dubey, Ashwani Tiwari, Pintu Kumar Mandal
Summary: An efficient and highly regioselective method has been developed for the synthesis of 3-indolyl-C-glycosides through coupling of glycosyl trichloroacetimidates with a wide range of substituted indoles in the presence of catalytic amounts of B(C6F5)(3) within a few minutes, providing exclusively beta-stereoselective products in 64-87% yields.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Mireia Sueca-Comes, Elena Cristina Rusu, Anna M. Grabowska, David O. Bates
Summary: The number of cancer drugs is increasing, but most research is still focused on a small subset of well-studied targets, with limited investigations into poorly studied kinases.
PHARMACOLOGICAL REVIEWS
(2022)
Article
Chemistry, Medicinal
You-Guang Zheng, Jin-An Wang, Long Meng, Xin Pei, Ling Zhang, Lin An, Cheng-Lin Li, Ying-Long Miao
Summary: In this study, a series of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives were designed and evaluated for their biological activities, with compound 10e showing potential as a candidate for cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Dalila Boi, Elisabetta Rubini, Sara Breccia, Giulia Guarguaglini, Alessandro Paiardini
Summary: Myc transcription factors play crucial roles in many cellular processes and its overexpression is frequently associated with cancer. The interplay between Myc and kinases is essential for tumor cell proliferation, with kinase inhibitors showing potential for cancer treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Simona Sestito, Andrea Bacci, Sara Chiarugi, Massimiliano Runfola, Francesca Gado, Eleonora Margheritis, Sheraz Gul, Maria E. Riveiro, Ramiro Vazquez, Samuel Huguet, Clementina Manera, Keyvan Rezai, Gianpiero Garau, Simona Rapposelli
Summary: Novel 2-oxindole-based derivatives were synthesized as dual PDK1-AurA kinase inhibitors, showing promising potential for treating Ewing sarcoma. Compound 12, the most potent one, is suitable for in vivo studies and presents nanomolar inhibitory potency against both PDK1 and AurA kinase.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Cindy Y. Ly, Jessica Pfannenstiel, Anil Pant, Zhilong Yang, Anthony R. Fehr, Maxim S. Rodzkin, David J. Davido
Summary: In this study, aurora kinase inhibitors were found to significantly reduce gene expression and viral replication of herpes simplex virus 1 (HSV-1). Furthermore, these inhibitors also showed inhibitory effects on the replication of other RNA and DNA viruses. These findings suggest a novel role for aurora kinases in the replication of diverse viruses.
MICROBIOLOGY SPECTRUM
(2023)
Review
Biochemistry & Molecular Biology
Francis Giraud, Elisabeth Pereira, Fabrice Anizon, Pascale Moreau
Summary: This review emphasizes the role of protein kinases as potential biological targets in pain management, categorizing them into different groups in the human kinome and describing examples of small molecule inhibitors demonstrating analgesic effects. It highlights the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.
Article
Biochemistry & Molecular Biology
Jiaqian Xu, Lijie Peng, Cuiping Guo, Fang Xu, Dong-Shi Lin, Yi Tang, Zhengqiu Li
Summary: Competitive proteome profiling is an effective approach for identifying small molecule targets and distinguishing genuine targets from non-specific labeling. In this study, an active probe derived from afatinib and a cysteine-reactive probe were used to compare their characterization of cellular targets, and MYH9 was identified as a potential target involved in the function of afatinib.
Article
Biology
Joan Gizzio, Abhishek Thakur, Allan Haldane, Ronald M. Levy
Summary: This study reveals the difference in binding affinity of tyrosine kinases (TKs) and serine/threonine kinases (STKs) to inhibitors is possibly due to the different conformational equilibrium of the activation loop. By calculating binding free energies and using sequence covariation analysis, the study estimates the free-energy costs for the conformational change of the activation loop and finds that TKs have smaller penalties for the folded activation loop conformation compared to STKs. The structure-based and sequence-based analyses provide molecular basis for this observation and have pharmacological implications for the selectivity of type-II inhibitors.
Article
Chemistry, Medicinal
Tao Jiang, Zhenhao Liu, Wenlang Liu, Jiawen Chen, Zheng Zheng, Mojie Duan
Summary: In this study, using metadynamics simulation, the conformational transition pathways of the DFG flipping for the c-Met kinase were analyzed. Two distinct pathways, DFG-up and DFG-down, were identified and their free energy profiles were calculated. The findings provide insights into the conformation-activity relationship for c-Met and may suggest a new drug target.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Review
Chemistry, Medicinal
Maria Antonietta Occhiuzzi, Gernando Lico, Giuseppina Ioele, Michele De Luca, Antonio Garofalo, Fedora Grande
Summary: The PI3K/PKB/mTOR signaling pathway has a well-known biochemical role in cell-cycle regulation. It becomes overactive during the development of cancer, promoting cell proliferation and inhibiting apoptosis. Therefore, targeting this pathway has become important in the treatment of various malignant tumors. Selective inhibitors have been identified, but drugs that target multiple proteins within the pathway have shown higher efficacy and limited drug resistance, making them promising anticancer agents. This survey focuses on small molecule drugs capable of modulating the PI3K/PKB/mTOR signaling pathway as potential pharmacological treatments for cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Xiaoli Pan, Junping Pei, Aoxue Wang, Wen Shuai, Lu Feng, Faqian Bu, Yumeng Zhu, Lan Zhang, Guan Wang, Liang Ouyang
Summary: This review provides an overview of the roles of the ERKs signaling pathway in cancer and the structure-activity relationships of small molecule inhibitors targeting ERKs. It offers important insights for drug design and optimization as well as potential therapeutic strategies to overcome drug resistance.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Biochemistry & Molecular Biology
Kei Segawa, Kazuhiko Igarashi, Kazutaka Murayama
Summary: The function of the transcription factor BACH1 is regulated by heme binding to multiple Cys-Pro (CP) motifs within its intrinsically disordered regions. The individual CP motifs contribute to the regulation of BACH1 activity by accepting heme in different coordination manners and their spatial locations are important for their individual functions. The presence of multiple CP motifs with distinct roles ensures the multifaceted, strict regulation of BACH1 by heme.
Article
Biology
Emily F. Ruff, Joseph M. Muretta, Andrew R. Thompson, Eric W. Lake, Soreen Cyphers, Steven K. Albanese, Sonya M. Hanson, Julie M. Behr, David D. Thomas, John D. Chodera, Nicholas M. Levinson
Article
Biochemistry & Molecular Biology
Aaron B. Edmund, Timothy F. Walseth, Nicholas M. Levinson, Lincoln R. Potter
Article
Biophysics
Benjamin P. Binder, Andrew R. Thompson, David D. Thomas
BIOPHYSICAL JOURNAL
(2019)
Article
Physiology
Yahor Savich, Benjamin P. Binder, Andrew R. Thompson, David D. Thomas
JOURNAL OF GENERAL PHYSIOLOGY
(2019)
Article
Cell Biology
Tory M. Schaaf, Evan Kleinboehl, Samantha L. Yuen, Lauren N. Roelike, Bengt Svensson, Andrew R. Thompson, Razvan L. Cornea, David D. Thomas
Article
Biochemistry & Molecular Biology
Abir Majumdar, David J. Burban, Joseph M. Muretta, Andrew R. Thompson, Tiffany A. Engel, Damien M. Rasmussen, Manu V. Subrahmanian, Gianluigi Veglia, David D. Thomas, Nicholas M. Levinson
Summary: CDKs are master regulators of the eukaryotic cell cycle, requiring regulatory phosphorylation and cyclin binding for activation. The study explores the activation process of Cdk2 and its allosteric coupling with different regulators, revealing differences between Cdk2 and Cdk4 in allosteric wiring and substrate specificity.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Thomas A. Bunch, Piyali Guhathakurta, Victoria C. Lepak, Andrew R. Thompson, Rhye-Samuel Kanassatega, Anna Wilson, David D. Thomas, Brett A. Colson
Summary: This study identified small-molecule inhibitors that affect the binding between cMyBP-C and actin, providing potential targets for heart failure drugs that mimic phosphorylation or disrupt interactions with actin/myosin. The fluorescence lifetime assay allowed for the detection of pharmacologically active compounds that interfere with cMyBP-C-actin binding. This validated high-throughput screen focused on cMyBP-C, a regulator of cardiac muscle contractility and a key factor in heart failure, for the first time.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Gina J. Park, Adam Osinski, Genaro Hernandez, Jennifer L. Eitson, Abir Majumdar, Marco Tonelli, Katie Henzler-Wildman, Krzysztof Pawlowski, Zhe Chen, Yang Li, John W. Schoggins, Vincent S. Tagliabracci
Summary: In this study, we reconstituted the formation mechanism of the SARS-CoV-2 RNA cap and identified key domains and interactions involved. This finding reveals a new target for the treatment of COVID-19.
Article
Biochemistry & Molecular Biology
Piyali Guhathakurta, Anna L. Carter, Andrew R. Thompson, Dillon Kurila, Jeffrey LaFrence, Li Zhang, Jake R. Trask, Bri Vanderheyden, Joseph M. Muretta, James M. Ervasti, David D. Thomas, Enrique De La Cruz
Summary: This article describes a novel high-throughput screening assay for the discovery of small molecules that increase the binding affinity between dystrophin and actin.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Erik B. Faber, Luxin Sun, Jian Tang, Emily Roberts, Sornakala Ganeshkumar, Nan Wang, Damien Rasmussen, Abir Majumdar, Laura E. Hirsch, Kristen John, An Yang, Hira Khalid, Jon E. Hawkinson, Nicholas M. Levinson, Vargheese Chennathukuzhi, Daniel A. Harki, Ernst Schonbrunn, Gunda I. Georg
Summary: Developing a selective CDK2 inhibitor has been challenging, but this study has identified a potent and selective CDK2 inhibitor that binds to an allosteric pocket, showing potential as a contraceptive.
NATURE COMMUNICATIONS
(2023)