Article
Chemistry, Medicinal
Mariola Stypik, Marcin Zagozda, Stanislaw Michalek, Barbara Dymek, Daria Zdzalik-Bielecka, Maciej Dziachan, Nina Orlowska, Pawel Gunerka, Pawel Turowski, Joanna Hucz-Kalitowska, Aleksandra Stanczak, Paulina Stanczak, Krzysztof Mulewski, Damian Smuga, Filip Stefaniak, Lidia Gurba-Bryskiewicz, Arkadiusz Leniak, Zbigniew Ochal, Mateusz Mach, Karolina Dzwonek, Monika Lamparska-Przybysz, Krzysztof Dubiel, Maciej Wieczorek
Summary: PI3K delta is a vital signaling molecule that regulates immune cell functions and plays a crucial role in various diseases. This study synthesized a library of selective inhibitors, and CPL302253 (54) showed the highest inhibitory potency, making it a potential candidate for asthma treatment.
Article
Chemistry, Medicinal
Mariola Stypik, Stanislaw Michalek, Nina Orlowska, Marcin Zagozda, Maciej Dziachan, Martyna Banach, Pawel Turowski, Pawel Gunerka, Daria Zdzalik-Bielecka, Aleksandra Stanczak, Urszula Kedzierska, Krzysztof Mulewski, Damian Smuga, Wioleta Maruszak, Lidia Gurba-Bryskiewicz, Arkadiusz Leniak, Wojciech Pietrus, Zbigniew Ochal, Mateusz Mach, Beata Zygmunt, Jerzy Pieczykolan, Krzysztof Dubiel, Maciej Wieczorek
Summary: A collection of new, potent, active, and selective PI3K delta inhibitors, with CPL302415 (6) showing the highest activity and good selectivity, have been synthesized in this study, potentially serving as candidate drugs for future clinical trials in SLE treatment.
Article
Biochemistry & Molecular Biology
Hao Lei, Weiming Duan, San-Qi Zhang, Yifan Feng, Mengyan Ma, Bo Yuan, Minhang Xin
Summary: This study presents a series of compounds with amino acid fragments as potent and selective PI3K delta inhibitors. Among them, compound A10 showed sub-nanomolar PI3Kd potency and strong antiproliferation effects against SU-DHL-6 cells. It was found that A10 tightly bound to PI3K delta protein with a planar-shaped conformation. This research suggests that using amino acid fragments as a new strategy for designing potent PI3K delta inhibitors.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
David M. Andrews, Sharon Cartic, Sabina Cosulich, Nullin Divecha, Paul Faulder, Vikki Flemington, Oliver Kern, Jason G. Kettle, Ellen MacDonald, Jennifer McKelvie, Kurt G. Pike, Bryan Roberts, Rachel Rowlinson, James M. Smith, Martin Stockley, Martin E. Swarbrick, Iris Treinies, Michael J. Waring
Summary: A novel and highly specific inhibitor of PIP5K has been discovered, which demonstrates potent biochemical and cellular activity, providing valuable insight into the role of PIP5K in human cancers.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Huanrong Bai, Jiajia Sun, Hao Lei, San-Qi Zhang, Bo Yuan, Mengyan Ma, Minhang Xin
Summary: This study investigated a series of pyrido[3,2-d]pyrimidine derivatives for their bioactivity, and compound S5 showed excellent enzyme activity and antiproliferation activity, making it a potential candidate for further investigation as a PI3K delta inhibitor.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Chemistry, Medicinal
Kenneth Down, Augustin Amour, Niall A. Anderson, Nick Barton, Sebastien Campos, Edward P. Cannons, Cole Clissold, Maire A. Convery, John J. Coward, Kevin Doyle, Birgit Duempelfeld, Christopher D. Edwards, Michael D. Goldsmith, Jana Krause, David N. Mallett, Grant A. McGonagle, Vipulkumar K. Patel, James Rowedder, Paul Rowland, Andrew Sharpe, Srividya Sriskantharajah, Daniel A. Thomas, Douglas W. Thomson, Sorif Uddin, J. Nicole Hamblin, Edith M. Hessel
Summary: Optimization of binding mode, removal of harmful substances, enhancement of potency and selectivity led to the discovery of a low dose and rat-toxicity suitable PI3K delta inhibitor for further development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Polymer Science
Hekun Ding, Qiongyue Zhang, Xingjin Yang, Qingge Feng, Dongbo Wang, Zheng Liu
Summary: By synthesizing the TAP-BPC/CN composite with desirable conductivity through mixing 2,4,6-triaminopyrimidine (TAP) doped melamine and biomass porous carbon (BPC), a new strategy for efficient photocatalysts with high absorption and photocatalysis in the antibiotic wastewater treatment is provided.
JOURNAL OF APPLIED POLYMER SCIENCE
(2023)
Article
Chemistry, Medicinal
Zenichi Ikeda, Taku Kamei, Yusuke Sasaki, Matthew Reynolds, Nozomu Sakai, Masato Yoshikawa, Michiko Tawada, Nao Morishita, Douglas R. Dougan, Chien-Hung Chen, Irena Levin, Hua Zou, Masako Kuno, Naoto Arimura, Yusuke Kikukawa, Mitsuyo Kondo, Kimio Tohyama, Kenjiro Sato
Summary: We explored a novel series of non-amidine-based C1s inhibitors. By replacing isoquinoline with 1-aminophthalazine, we enhanced the C1s inhibitory activity while maintaining good selectivity against other serine proteases. Through structure-based optimization around the S2 and S3 sites and improving membrane permeability, we identified (R)-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor, which effectively blocked the classical complement pathway.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Xi Zhang, Yu-ting Duan, Yi Wang, Xing-dong Zhao, Yi-ming Sun, Dong-ze Lin, Yi Chen, Yu-xiang Wang, Zu-wen Zhou, Yan-xin Liu, Li-hua Jiang, Mei-yu Geng, Jian Ding, Ling-hua Meng
Summary: The novel PI3K delta inhibitor SAF-248 exhibits high selectivity for PI3K delta and superior antiproliferative activity against DLBCL cells. It induces cell apoptosis by blocking PI3K signaling and shows dose-dependent inhibition of xenograft growth. Co-targeting mTORC1, MYC, and JAK/STAT signaling pathways enhances SAF-248's activity, making it a promising treatment option for DLBCL.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Chemistry, Physical
R. Thirumurugan, K. Anitha
Summary: A hydrous organic salt of 2,4,6-triaminopyrimidine-1,3-diium L-tartrate monohydrate (TTM) was synthesized and its structural features, intermolecular interactions, vibrational modes, and NLO properties were investigated through various analytical techniques. The relationship between molecular structure and properties of TTM was systematically studied using density functional theory (DFT) calculations.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Chemistry, Medicinal
Jifeng Qi, Weihua Wang, Yongmei Tang, Shengying Lou, Jiaer Wang, Tao Yuan, Qiaojun He, Bo Yang, Hong Zhu, Sunliang Cui
Summary: PI3K delta inhibitors with a new chemical structure show superior efficacy and mechanism in the treatment of hepatocellular carcinoma.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xiao-Kang Guo, Yingkai Zhang
Summary: This study developed an integrated computational protocol to curate covalent binders from the RCSB Protein Data Bank, providing a foundation for the design of covalent modulators.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Inorganic & Nuclear
Mohd Faizan, Mohd Mehkoom, Ziya Afroz, Vitor Hugo Nunes Rodrigues, S. M. Afzal, Shabbir Ahmad
Summary: A newly synthesized dihydrated organic crystal of TAP(+)DNB(-).2H(2)O was successfully grown and characterized in this study, with a focus on its structural and optical properties. Various analytical techniques were employed to investigate the crystal's potential applications, with results indicating promise for practical use. An integrated approach combining experimental and theoretical methods has provided a comprehensive understanding of this molecular complex.
JOURNAL OF SOLID STATE CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Iain A. Cumming, Sebastien L. Degorce, Anna Aagaard, Erin L. Braybrooke, Nichola L. Davies, Coura R. Diene, Andrew J. Eatherton, Hannah R. Felstead, Sam D. Groombridge, Eva M. Lenz, Yunxia Li, Youfeng Nai, Stuart Pearson, Graeme R. Robb, James S. Scott, Oliver R. Steward, Chengyan Wu, Yafeng Xue, Lanping Zhang, Yanxiu Zhang
Summary: This article reports the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. By switching the pyridine ring for an N-substituted pyridone, a novel hinge binding scaffold was obtained, which retained potency against IRAK4. Introduction of the carbonyl and establishment of an internal hydrogen bond with the 4-NH allowed truncation of the large basic substituent to a 1-methylcyclopyl group.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jingyu Zhu, Lei Jia, Yingmin Jiang, Qianqian Yu, Lei Xu, Yanfei Cai, Yun Chen, Huazhong Li, Huang Gang, Wenqing Liang, Jian Jin
Summary: This study employs a modeling strategy integrating 3D-QSAR, pharmacophore model, and molecular dynamics simulation to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3K delta. The CoMFA model with high statistical significance was constructed to uncover the general structure-activity relationships, while a reliable pharmacophore model with robust discrimination capability was built to elucidate the main chemical characteristics of PI3K delta inhibitors. Molecular dynamics simulation was conducted to explore the binding modes and some key residues, highlighting delta-selective binding.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)