journal
https://read.qxmd.com/read/39021163/correction-to-discovery-of-novel-acridane-based-tubulin-polymerization-inhibitors-with-anticancer-and-potential-immunomodulatory-effects
#21
Xiaopeng Peng, Yichang Ren, Wanyi Pan, Jin Liu, Jianjun Chen
No abstract text is available yet for this article.
July 18, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39018526/discovery-of-gs-7682-a-novel-4-cyano-modified-c-nucleoside-prodrug-with-broad-activity-against-pneumo-and-picornaviruses-and-efficacy-in-rsv-infected-african-green-monkeys
#22
JOURNAL ARTICLE
Dustin S Siegel, Hon C Hui, Jared Pitts, Meghan S Vermillion, Kazuya Ishida, Davin Rautiola, Michael Keeney, Hammad Irshad, Lijun Zhang, Kwon Chun, Gregory Chin, Bindu Goyal, Edward Doerffler, Hai Yang, Michael O Clarke, Chris Palmiotti, Arya Vijjapurapu, Nicholas C Riola, Kirsten Stray, Eisuke Murakami, Bin Ma, Ting Wang, Xiaofeng Zhao, Yili Xu, Gary Lee, Bruno Marchand, Minji Seung, Arabinda Nayak, Adrian Tomkinson, Nani Kadrichu, Scott Ellis, Ona Barauskas, Joy Y Feng, Jason K Perry, Michel Perron, John P Bilello, Philip J Kuehl, Raju Subramanian, Tomas Cihlar, Richard L Mackman
Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 ( 1 ), a novel phosphoramidate prodrug of a 4'-CN-4-aza-7,9-dideazaadenosine C -nucleoside GS-646089 ( 2 ) with broad antiviral activity against RSV (EC50 = 3-46 nM), human metapneumovirus (EC50 = 210 nM), human rhinovirus (EC50 = 54-61 nM), and enterovirus (EC50 = 83-90 nM)...
July 17, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39018425/predicting-the-intravenous-pharmacokinetics-of-covalent-drugs-in-animals-and-humans
#23
JOURNAL ARTICLE
Rowan Stringer, Tobias Kaster
30 covalent drugs were used to assess clearance (CL) prediction reliability in animals and humans. In animals, marked CL underprediction was observed using cryopreserved hepatocytes or liver microsomes (LMs) supplemented for cytochrome P450 activity. Improved quantitative performance was observed by combining metabolic stability data from LMs and liver S9 fractions, the latter supplemented with reduced glutathione for glutathione transferase activity. While human LMs provided reliable human CL predictions, prediction statistics were improved further by incorporating S9 stability data...
July 17, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39018123/detection-of-a-mitochondrial-fragmentation-and-integrated-stress-response-using-the-cell-painting-assay
#24
JOURNAL ARTICLE
Soheila Rezaei Adariani, Daya Agne, Sandra Koska, Annina Burhop, Carina Seitz, Jens Warmers, Petra Janning, Malte Metz, Axel Pahl, Sonja Sievers, Herbert Waldmann, Slava Ziegler
Mitochondria are cellular powerhouses and are crucial for cell function. However, they are vulnerable to internal and external perturbagens that may impair mitochondrial function and eventually lead to cell death. In particular, small molecules may impact mitochondrial function, and therefore, their influence on mitochondrial homeostasis is at best assessed early on in the characterization of biologically active small molecules and drug discovery. We demonstrate that unbiased morphological profiling by means of the cell painting assay (CPA) can detect mitochondrial stress coupled with the induction of an integrated stress response...
July 17, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39016216/discovery-synthesis-and-activity-evaluation-of-novel-five-membered-sulfur-containing-heterocyclic-nucleosides-as-potential-anticancer-agents-in-vitro-and-in-vivo
#25
JOURNAL ARTICLE
Er-Jun Hao, Yan Zhao, Min Yu, Xian-Jia Li, Ke-Xin Wang, Fu-Ying Su, Yu-Ru Liang, Yang Wang, Hai-Ming Guo
A series of novel five-membered sulfur-containing heterocyclic nucleoside derivatives were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship studies revealed that some of them showed obvious antitumor activities in several cancer cell lines. Among them, compound 22o exhibited remarkable antiproliferative activity against HeLa cells and was more potent than cisplatin (IC50 = 2.80 vs 7.99 μM). Furthermore, mechanism studies indicated that 22o inhibited cell metastasis, induced cell apoptosis, decreased mitochondrial membrane potential, and activated autophagy through the PI3K-Akt-mTOR signaling pathway...
July 17, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39013156/fap-radioligand-linker-optimization-improves-tumor-dose-and-tumor-to-healthy-organ-ratios-in-4t1-syngeneic-model
#26
JOURNAL ARTICLE
Spencer D Lindeman, Owen C Booth, Pooja Tudi, Taylor C Schleinkofer, Jackson N Moss, Nicholas B Kearney, Ramesh Mukkamala, Lauren K Thompson, Mollie A Modany, Madduri Srinivasarao, Philip S Low
Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39013123/addressing-the-opioids-lipophilicity-challenge-via-a-straightforward-and-simultaneous-1-h-nmr-based-log-p-d-determination-both-separately-and-in-mixtures
#27
JOURNAL ARTICLE
Dina Yeffet, Ishay Columbus, Galit Parvari, Yoav Eichen, Sigal Saphier, Lee Ghindes-Azaria, Orit Redy-Keisar, Dafna Amir, Eyal Drug, Eytan Gershonov, Iris Binyamin, Yoram Cohen, Naama Karton-Lifshin, Yossi Zafrani
A systematic study of trends in the lipophilicity of prominent representatives of the opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1 H NMR-based log P / D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous log D determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact Δlog D values of matched pairs is required...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39013072/molecular-transformers-adaptive-multitarget-ligands-for-esterase-induced-transition-from-analgesics-to-anesthetics
#28
JOURNAL ARTICLE
Tianguang Huang, Chi Song, Yuhao Chen, Yu Gan, Shilong Hu, Ao Hai, Wencheng Liu, Ting Kang, Yi Zhao, Zhuang Miao, Xing Wang, Yihang Fu, Bowen Ke
Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39013034/design-synthesis-and-biological-evaluation-of-1-4-dihydropyridine-indole-as-a-potential-antidiabetic-agent-via-glut4-translocation-stimulation
#29
JOURNAL ARTICLE
Sarita Katiyar, Shadab Ahmad, Abhishek Kumar, Alisha Ansari, Amol Chhatrapati Bisen, Ishbal Ahmad, Farah Gulzar, Rabi Sankar Bhatta, Akhilesh K Tamrakar, Koneni V Sashidhara
In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine-indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4 myc myotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, 12 , 14 , 15 , 16 , 19 , 27 , and 35 demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39013015/development-of-zalfermin-a-long-acting-proteolytically-stabilized-fgf21-analog
#30
JOURNAL ARTICLE
Kristian Sass-Ørum, Tina Møller Tagmose, Jørgen Olsen, Annika Sjölander, Per-Olof Wahlund, Dan Han, Andreas Vegge, Steffen Reedtz-Runge, Zhe Wang, Xiang Gao, Birgit Wieczorek, Kasper Lamberth, Kirsten Lykkegaard, Peter Kresten Nielsen, Henning Thøgersen, Mingrui Yu, Jianhua Wang, Jørn Drustrup, Xujia Zhang, Patrick Garibay, Kristian Hansen, Ann Maria Kruse Hansen, Birgitte Andersen
Here, we describe the development of the FGF21 analog zalfermin (NNC0194-0499, 15 ), intended for once-weekly sc dosing. Protein engineering was needed to address inherent druggability issues of the natural FGF21 hormone. Thus, deamidation of Asp121 was solved by mutation to glutamine, and oxidation of Met168 was solved by mutation to leucine. N-terminal region degradation by dipeptidyl peptidase IV was prevented by alanine residue elongation. To prevent inactivating metabolism by fibroblast activation protein and carboxypeptidase-like activity in the C-terminal region, and to achieve t 1/2 extension (53 h in cynomolgus monkeys), we introduced a C18 fatty diacid at the penultimate position 180...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39012838/discovery-of-biphenyl-derivatives-to-target-hsp70-bim-protein-protein-interaction-in-chronic-myeloid-leukemia-by-scaffold-hopping-strategy
#31
JOURNAL ARTICLE
Maojun Jiang, Hong Zhang, Yang Song, Fangkui Yin, Zhiyuan Hu, Xin Li, Yuying Wang, Zheming Wang, Yitong Li, Zihan Wang, Yanxin Zhang, Siyao Wang, Shaohua Lu, Guanghong Xu, Ting Song, Ziqian Wang, Zhichao Zhang
Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10 , the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression ( K d = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39012026/correction-to-discovery-of-novel-and-highly-potent-resorcinol-dibenzyl-ether-based-pd-1-pd-l1-inhibitors-with-improved-drug-like-and-pharmacokinetic-properties-for-cancer-treatment
#32
Binbin Cheng, Wei Wang, Xiaoge Niu, Yichang Ren, Ting Liu, Hao Cao, Shuanghu Wang, Yingfeng Tu, Jingxuan Chen, Shuwen Liu, Xuchao Yang, Jianjun Chen
No abstract text is available yet for this article.
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39011823/erap-inhibitors-in-autoimmunity-and-immuno-oncology-medicinal-chemistry-insights
#33
REVIEW
Vasileios Fougiaxis, Ben He, Tuhina Khan, Rodolphe Vatinel, Nikoletta M Koutroumpa, Antreas Afantitis, Laetitia Lesire, Pierre Sierocki, Benoit Deprez, Rebecca Deprez-Poulain
Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors...
July 16, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39010658/structure-based-design-and-discovery-of-a-potent-and-cell-active-lc3a-b-covalent-inhibitor
#34
JOURNAL ARTICLE
Zhenfei Zhou, Siqi Huang, Shijie Fan, Xueyuan Li, Chengyu Wang, Wanlin Yu, Daohai Du, Yuanyuan Zhang, Kaixian Chen, Wei Fu, Cheng Luo
Autophagy is a highly conserved cellular homeostasis maintenance mechanism in eukaryotes. Microtubule-associated protein light chain 3 (LC3) plays a crucial role in autophagy. It has multiple pairs of protein-protein interactions (PPIs) with other proteins, and these PPIs have an effect on the regulation of autophagosome formation and the recruitment of autophagic substrates. In our previous work, a small molecule covalent inhibitor DC-LC3in-D5 which could inhibit LC3A/B PPIs was identified, but a detailed study of structure-activity relationships (SARs) was lacking...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39009572/multifunctional-molecular-hybrids-photoreleasing-nitric-oxide-advantages-pitfalls-and-opportunities
#35
REVIEW
Cristina Parisi, Francesca Laneri, Aurore Fraix, Salvatore Sortino
The multifaceted role nitric oxide (NO) plays in human physiology and pathophysiology has opened new scenarios in biomedicine by exploiting this free radical as an unconventional therapeutic against important diseases. The difficulties in handling gaseous NO and the strict dependence of the biological effects on its doses and location have made the light-activated NO precursors, namely NO photodonors (NOPDs), very appealing by virtue of their precise spatiotemporal control of NO delivery. The covalent integration of NOPDs and additional functional components within the same molecular skeleton through suitable linkers can lead to an intriguing class of multifunctional photoactivatable molecular hybrids...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39009041/chasing-red-herrings-palladium-metal-salt-impurities-feigning-kras-activity-in-biochemical-assays
#36
JOURNAL ARTICLE
Thomas Gerstberger, Helmut Berger, Frank H Büttner, Michael Gmachl, Dirk Kessler, Manfred Koegl, Simon Lucas, Laetitia J Martin, Moriz Mayer, Darryl B McConnell, Sophie Mitzner, Guido Scholz, Matthias Treu, Bernhard Wolkerstorfer, Stephan Zahn, Krzysztof M Zak, Philipp A Jaeger, Peter Ettmayer
Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39008565/discovery-of-a-highly-potent-lysine-methyltransferases-g9a-nsd2-dual-inhibitor-to-treat-solid-tumors
#37
JOURNAL ARTICLE
Chunju Yang, Bang Li, Zongbo Feng, Huaxuan Li, Hong Yang, Zhenjiao Yang, Li Liu, Qiongyu Shi, Hong Wang, Zhong-Zhu Chen, Xun Huang, Junjian Wang, Yuanxiang Wang
Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15 ...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39007759/identification-of-6-anilino-imidazo-4-5-c-pyridin-2-ones-as-selective-dna-dependent-protein-kinase-inhibitors-and-their-application-as-radiosensitizers
#38
JOURNAL ARTICLE
Cho R Hong, Lydia P Liew, Way W Wong, Benjamin D Dickson, Gary Cheng, Avik Shome, Rebecca Airey, Jagdish Jaiswal, Barbara Lipert, Stephen M F Jamieson, William R Wilson, Michael P Hay
The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5- c ]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39005064/electrophile-determines-cellular-phenotypes-among-xpo1-targeting-small-molecules
#39
JOURNAL ARTICLE
Yi Fan Chen, Yanqiu Shen, David F Yan, Maryam Ghazala, Marc A Scemama de Gialluly, Ramya Srinivasan, Amanda N Farrar, Ryan M Friedrich, Drew J Adams
Covalent drug discovery has experienced a renaissance, with numerous electrophilic small molecules recently gaining FDA approval. Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019. Emerging evidence supports additional pharmacological classes of XPO1 modulators targeting Cys528, including the selective inhibitors of transcriptional activation (SITAs) and probes that induce rapid degradation of XPO1...
July 15, 2024: Journal of Medicinal Chemistry
https://read.qxmd.com/read/39004939/identification-of-a-novel-protein-phosphatase-2a-activator-ppa24-as-a-potential-therapeutic-for-folfox-resistant-colorectal-cancer
#40
JOURNAL ARTICLE
Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M Sha, Jian Wang, Krishne Gowda, Zhihang Shen, Haritha Nair, Chenglong Li, Nikolay V Dokholyan, Satya Narayan, Arun K Sharma
A series of compounds were designed utilizing molecular modeling and fragment-based design based upon the known protein phosphatase 2A (PP2A) activators, NSC49L and iHAP1 , and evaluated for their ability to inhibit the viability of colorectal cancer (CRC) and folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX)-resistant CRC cells. PPA24 ( 19a ) was identified as the most cytotoxic compound with IC50 values in the range of 2.36-6.75 μM in CRC and FOLFOX-resistant CRC cell lines. It stimulated PP2A activity to a greater extent, displayed lower binding energies through molecular docking, and showed higher binding affinity through surface plasmon resonance for PP2A catalytic subunit α than the known PP2A activators...
July 14, 2024: Journal of Medicinal Chemistry
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