Article
Biochemistry & Molecular Biology
Mehmet Karatas, Apirat Chaikuad, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan Knapp, Conrad Kunick
Summary: This study successfully synthesized new compounds with dual inhibitory effects on Aurora A kinase and VEGF receptor kinases by formally dissecting and reassembling the basic structure of a known inhibitor class. Crystal structures of the new compounds in complex with Aurora A provided insights for rational structural modifications, and in vitro screening showed anti-proliferative activity in cancer cell lines.
Article
Medicine, Research & Experimental
Di Chen, Elizabeth D. Hughes, Thomas L. Saunders, Jiangping Wu, Magda N. Hernandez Vasquez, Taija Makinen, Philip D. King
Summary: This study demonstrates that RASA1 and EPHB4 function in the same signaling pathway to protect against the development of CM-AVM, independent of physical interaction. These findings have important implications for possible treatment of this disease.
Article
Pharmacology & Pharmacy
Hannah A. Blair
Summary: Belumosudil, a ROCK inhibitor developed by Kadmon Pharmaceuticals, has received its first approval in the USA for the treatment of cGVHD. Regulatory reviews are underway in other countries, and clinical development for systemic sclerosis is ongoing in the USA.
Article
Multidisciplinary Sciences
Jinxin Li, Huimin Sun, Meiling Fu, Zeyuan Zheng, Chunlan Xu, Kunao Yang, Yankuo Liu, Zuodong Xuan, Yang Bai, Jianzhong Zheng, Yue Zhao, Zhiyuan Shi, Chen Shao
Summary: This study demonstrates that high expression of TOPK in RCC promotes PD-L1 expression by activating ERK2 and TGF-beta/Smad pathways. TOPK is also shown to inhibit CD8(+) T cell infiltration and function, promoting immune escape in RCC. Inhibition of TOPK enhances CD8(+) T cell infiltration, activation, anti-PD-L1 therapeutic efficacy, and synergistically enhances anti-RCC immune response.
Article
Chemistry, Medicinal
Seungbeom Lee, Jisu Kim, Jeyun Jo, Jae Won Chang, Jaehoon Sim, Hwayoung Yun
Summary: Bivalent kinase inhibitors have emerged as a promising approach for targeting specific kinases with enhanced selectivity and affinity through increased interactions with target enzymes. Recent developments have led to the creation of bivalent compounds with high kinase affinity, biological and chemical stability in vivo, offering significant potential for therapeutic applications. This review provides a comprehensive overview of hetero-bivalent kinase inhibitors and discusses their advantages, limitations, and future prospects compared to monovalent kinase inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Andras Piffko, Christian Uhl, Peter Vajkoczy, Marcus Czabanka, Thomas Broggini
Summary: EphrinB2-EphB4 signaling plays critical roles in embryogenesis and cancer pathologies. This signaling is involved in various cancer processes, such as migration, angiogenesis, and metastasis. However, the signaling pathways differ depending on the cancer type. This study explores the impact of these signaling pathways in neurooncological diseases, including glioma and brain metastasis, and seeks to understand their role in antiangiogenic therapy resistance, particularly in glioma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biotechnology & Applied Microbiology
Hannah I. Ghasemi, Julien Bacal, Amanda C. Yoon, Katherine U. Tavasoli, Carmen Cruz, Jonathan T. Vu, Brooke M. Gardner, Chris D. Richardson
Summary: The efficiency of gene editing via homology-directed repair (HDR) can be enhanced by covalently modifying the template DNA to form interstrand crosslinks. These crosslinked templates (xHDRTs) significantly increase Cas9-mediated editing efficiencies in various cell types. The increased editing from xHDRTs is dependent on events occurring on the template molecule and requires the ATR kinase and components of the Fanconi anemia pathway.
NATURE BIOTECHNOLOGY
(2023)
Article
Multidisciplinary Sciences
R. Charles Coombes, Sacha Howell, Simon R. Lord, Laura Kenny, Janine Mansi, Zahi Mitri, Carlo Palmieri, Linnea I. Chap, Paul Richards, William Gradishar, Sagar Sardesai, Jason Melear, Joyce O'Shaughnessy, Patrick Ward, Pavani Chalasani, Tobias Arkenau, Richard D. Baird, Rinath Jeselsohn, Simak Ali, Glen Clack, Ashwani Bahl, Stuart McIntosh, Matthew G. Krebs
Summary: This study reports the clinical trial results of samuraciclib as an anti-cancer treatment, showing its clinical activity in patients with triple negative breast cancer and HR+/HER2- breast cancer.
NATURE COMMUNICATIONS
(2023)
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
Medicine, Research & Experimental
Oliver Lyons, James Walker, Christopher Seet, Mohammed Ikram, Adam Kuchta, Andrew Arnold, Magda Hernandez-Vasquez, Maike Frye, Gema Vizcay-Barrena, Roland A. Fleck, Ashish S. Patel, Soundrie Padayachee, Peter Mortimer, Steve Jeffery, Siren Berland, Sahar Mansour, Pia Ostergaard, Taija Makinen, Bijan Modarai, Prakash Saha, Alberto Smith
Summary: The study revealed that mutations in the EPHB4 gene can affect the formation of venous valves, leading to deep venous reflux in patients. Deletion of the Efnb2 gene disrupts normal endothelial expression patterns, affecting the development and proliferation of valve-forming cells.
Review
Biochemistry & Molecular Biology
Lianbo Li, Cynthia Meyer, Zhi-Wei Zhou, Ammar Elmezayen, Kenneth Westover
Summary: Allosteric mechanisms are common in nature but rare in human-designed perturbagens. The development of KRAS(G12C) inhibitors suggests that covalent chemistry could expand the use of allosteric inhibitors. This study explores the feasibility of extending this approach to other proteins in the RAS and kinase family, which play important roles in cellular processes, especially in cancer therapy.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Oncology
Jun-Cheng Wang, Dong-Ping Chen, Shi-Xun Lu, Jin-Bin Chen, Yuan Wei, Xue-Chao Liu, Yu-Hao Tang, Rongxin Zhang, Jian-Cong Chen, Anna Kan, Li Xu, Yao-Jun Zhang, Jiajie Hou, Dong-Ming Kuang, Min -Shan Chen, Zhong-Guo Zhou
Summary: The proto-oncogene serine/threonine protein kinase PIM2 acts as a negative regulator of tumor inflammation, hindering the efficacy of cancer immunotherapy. IL1(3 derived from tumor macrophages triggers PIM2 expression in cancer cells, leading to their aggressive features. Inhibiting IL1(3 or PIM2 kinase combined with immune checkpoint blockade effectively induces tumor regression.
Review
Pharmacology & Pharmacy
Connie Kang
Summary: Infigratinib, a FGFR-specific tyrosine kinase inhibitor, has been approved in the USA for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with specific genetic abnormalities.
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)
Article
Chemistry, Medicinal
Younho Lee, Hyunkyung Kim, Haelee Kim, Ha Yeon Cho, Jun-Goo Jee, Kyung-Ah Seo, Jung Beom Son, Eunhwa Ko, Hwan Geun Choi, Nam Doo Kim, Ikyon Kim
Summary: A highly selective MPS1 inhibitor based on a specific scaffold was developed and optimized guided by key X-ray crystal structure analysis, showing effective inhibition of TNBC cell proliferation in in vivo evaluation.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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)