Review
Chemistry, Medicinal
Zheng Zhao, Philip E. Bourne
Summary: This article reviews the recent developments in covalent kinase inhibitors (CKIs) and discusses their characteristics, including the features of nucleophilic amino acids and preferences of electrophilic warheads. It also explores trends in CKI development across the whole proteome.
Review
Pharmacology & Pharmacy
Yi Chen, Zhi-Zheng Wang, Ge-Fei Hao, Bao-An Song
Summary: Kinases play a crucial role in cell signaling, and kinase inhibitors have significant potential as new therapeutics. In recent years, an increasing amount of computational resources have been developed to design kinase inhibitors more efficiently, providing a learning platform for nonspecialists.
DRUG DISCOVERY TODAY
(2022)
Article
Chemistry, Medicinal
Rammohan R. Yadav Bheemanaboina, Mariana Laureano de Souza, Mariana Lozano Gonzalez, Shams Ul Mahmood, Tyler Eck, Tamara Kreiss, Samantha O. Aylor, Alison Roth, Patricia Lee, Brandon S. Pybus, Dennis J. Colussi, Wayne E. Childers, John Gordon, John J. Siekierka, Purnima Bhanot, David P. Rotella
Summary: This paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Fei Hou, Yuhong Yao, Yujiao Wei, Yubo Wang, Yangzi Cao, Xinqiang Liu, Liting Zheng, Qingqing Zhang, Yue Jiao, Yukun Chen, Yue Meng, Yue Sun, Yanjie Wu, Jiefu Wang, Junfeng Wang, Zhou Wu, Kun Zhang, Mingming Wei, Guang Yang
Summary: A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared as potential inhibitors of VEGFR-2 using 3D modeling. Compound I10 showed more potent inhibitory activity (IC50 = 0.11 nM) against VEGFR-2 compared to most listed drugs, and it was confirmed as a selective VEGFR-2 inhibitor. 3D modeling predicted a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable antiangiogenesis and anti-proliferation effects in HUVEC at low nanomolar concentrations, and PK studies showed adequate oral bioavailability. In vivo subcutaneous tumor model demonstrated potent efficacy of I10 in inhibiting tumor growth and angiogenesis, indicating its potential as a drug candidate for cancer treatment.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Preeti Gupta, Aaliya Taiyab, Afzal Hussain, Mohamed F. Alajmi, Asimul Islam, Md. Imtaiyaz Hassan
Summary: Cancer is a leading cause of global mortality, with SphK1 and its metabolite S1P being potential therapeutic targets due to their over-expression in various cancers and metabolic disorders. This review discusses the sphingolipid metabolism and the role of SphK isoforms in human malignancies, as well as the potential of SphK inhibitors in cancer therapy. It highlights the importance of sphingolipid metabolites in regulating physiological processes and the significance of the SphK/S1P signaling axis in human pathologies.
Article
Chemistry, Medicinal
Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu, Frederic Vallee, Marie-Eve Leclaire, Jimmy Fourtounis, Giovanni Martino, Alexander L. Perryman, Victor Pau, Shou Yun Yin, Pavel Mader, Anne Roulston, Jean-Francois Truchon, C. Gary Marshall, Mohamed Diallo, Nicole M. Duffy, Rino Stocco, Claude Godbout, Alexanne Bonneau-Fortin, Rosie Kryczka, Vivek Bhaskaran, Daniel Mao, Stephen Orlicky, Patrick Beaulieu, Pascal Turcotte, Igor Kurinov, Frank Sicheri, Yael Mamane, Michel Gallant, W. Cameron Black
Summary: PKMYT1 acts as a regulator of CDK1 phosphorylation and has been identified as a potential therapeutic target for certain types of DNA damage response cancers. In this study, a weak inhibitor of PKMYT1 was identified and further optimized using structure-based drug design to improve its potency. The resulting potent and selective inhibitors, such as RP 6306, showed inhibitory effects on CCNE1-amplified tumor cell growth in preclinical xenograft models. RP 6306 is currently being evaluated in Phase 1 clinical trials for the treatment of various solid tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Pharmacology & Pharmacy
You-Cai Xiao, Fen-Er Chen
Summary: Vinyl sulfones play important roles in drug discovery as structural motifs and versatile building blocks. They target various macromolecular targets and have been applied in the design of anticancer, anti-infective, anti-inflammatory, and neuroprotective agents. However, further improvement is needed in terms of drug-like properties and the chemical space of vinyl sulfones.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Pharmacology & Pharmacy
Han Wee Ong, Jack Adderley, Andrew B. Tobin, David H. Drewry, Christian Doerig
Summary: The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2023)
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)
Review
Chemistry, Medicinal
Wenxin Luo, Yilin Gu, Siyu Fu, Jiaxing Wang, Jifa Zhang, Yuxi Wang
Summary: Idiopathic pulmonary fibrosis (IPF) is a common fibrotic lung disease with limited treatment options. Recent advancements in understanding the mechanisms of IPF have led to the development of novel drugs, and some promising next-generation IPF drugs are currently in clinical trials.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Aishah M. Alsibaee, Hanan M. Al-Yousef, Huda S. Al-Salem
Summary: Quinazolines are nitrogen-containing heterocycles that consist of a benzene ring fused with a pyrimidine ring. Quinazolinones, which are oxidized quinazolines, have significant biological activities and are building blocks in pharmaceuticals. Scientists are interested in quinazolinones due to their stability, easy preparation methods, and ability to penetrate the blood-brain barrier. The positions 2, 6, and 8 of the quinazolinone ring system are important for their pharmacological activities.
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
Genetics & Heredity
Hammad Naveed, Corinna Reglin, Thomas Schubert, Xin Gao, Stefan T. Arold, Michael L. Maitland
Summary: The study introduces iDTPnd, a computational approach for large-scale discovery of novel drug targets. The method provides a docking-based interaction score for evaluating unintended targets and successfully validated interactions of several drugs with known targets, as well as predicting and validating new potential targets.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2021)
Review
Biotechnology & Applied Microbiology
Alexander A. Peterson, David R. Liu
Summary: DNA-encoded library (DEL) technology is a powerful small-molecule discovery platform, offering many advantages over traditional screening methods. This Review provides accounts of recently described small molecules discovered from DELs, illustrating the versatility, efficiency and broad impact of this technology.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Xueyan Sun, Yijiao Peng, Jingduo Zhao, Zhizhong Xie, Xiaoyong Lei, Guotao Tang
Summary: Tumor cells primarily rely on aerobic glycolysis for energy, and inhibiting the three main rate-limiting enzymes in glycolysis is considered an important strategy for cancer treatment. The development of inhibitors targeting these enzymes is a focus of research for potential therapeutic interventions.
BIOORGANIC CHEMISTRY
(2021)