Bioorganic & Medicinal Chemistry最新文献

{"title":"Synthesis of kanamycin-azole hybrids and investigation of their antifungal activities","authors":"Naveena Poudyal ,&nbsp;Yagya P. Subedi ,&nbsp;Madyson Shakespear ,&nbsp;Michelle Grilley ,&nbsp;Jon Y. Takemoto ,&nbsp;Cheng-Wei T. Chang","doi":"10.1016/j.bmc.2024.117947","DOIUrl":"10.1016/j.bmc.2024.117947","url":null,"abstract":"<div><div>The World Health Organization (WHO) recognizes <em>Candida albicans</em> and <em>Cryptococcus neoformans</em> as the critical priority fungal pathogens for which therapeutic solutions are needed. Azole-based antifungal agents, including triazoles, diazoles, and thiazoles, are widely used in the treatments for fungal infections. In light of past successes in the transformation of antibacterial kanamycin into antifungal derivatives via chemical modifications, a new library of kanamycin-azole hybrids was synthesized and tested against a panel of azole-resistant and susceptible <em>Candida</em> and <em>Cryptococcus</em> strains. Structure activity relationship (SAR) studies revealed pivotal roles for antifungal activity of the azole ring (imidazole vs triazole) and halogen substituents on the benzene ring (F vs Cl). Most notably, hybrids <strong>13, 14</strong> and <strong>15</strong> were active against resistant <em>C. albicans</em>, <em>C. tropicalis</em> and <em>C. neoformans</em> strains and non-toxic towards mammalian cells. Mode of action investigations using fluorogenic dyes, (SYTOX^TM) showed the fungal active compounds could permeabilize fungal membranes even at ¼ MICs. These findings reveal novel azole-based antifungals that could offer new therapeutic options for candidiasis and cryptococcosis.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117947"},"PeriodicalIF":3.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of LPS-induced inflammatory response in RAW264.7 cells by natural Chlorogenic acid isomers involved with AKR1B1 inhibition","authors":"Xu Han ,&nbsp;Xiaqing Wu ,&nbsp;Fanglin Liu ,&nbsp;Huan Chen ,&nbsp;Hongwei Hou","doi":"10.1016/j.bmc.2024.117942","DOIUrl":"10.1016/j.bmc.2024.117942","url":null,"abstract":"<div><div>Inflammation is the physiological response of the immune system to injury or infection, typically manifested by local tissue congestion, swelling, heat, and pain. Prolonged or excessive inflammation can lead to tissue damage and the development of many diseases. The anti-inflammatory effects of natural ingredients have been extensively researched and confirmed. This study investigated the effects of Chlorogenic acid (CGA) isomers —— 3-Caffeolyquninic acid (3-CQA), 4-Caffeolyquninic acid (4-CQA), and 5-Caffeolyquninic acid (5-CQA) —— on the inflammatory response and oxidative stress reaction induced by LPS in RAW264.7 cells. Overall, 3-CQA exhibited the most significant reduction in levels of TNF-α, IL-6, NO, and ROS. 4-CQA showed superior inhibition of TNF-α compared to 5-CQA (p &lt; 0.05), while no significant difference in other parameters. We further used DARTS and CETSA to demonstrate that CGA isomers have stable affinity with AKR1B1. As a positive control, the AKR1B1 antagonist epalrestat exhibited similar effects to the CGA isomers. 3-CQA having the smallest half-inhibitory concentration (IC50) for AKR1B1, while 4-CQA and 5-CQA have similar values. AutoDock simulations of the docking conformations revealed minimal differences in the average binding energies of the CGA isomers. The main differences were that VAL47 formed a hydrogen bond with 3-CQA, whereas GLN49 formed hydrogen bonds with 4-CQA and 5-CQA. Additionally, the number of hydrophobic bonds involving PHE122 and LEU300 varies. Our conclusion is that differences in non-covalent interactions result in the varying inhibitory abilities of CGA isomers on AKR1B1, which further affect the anti-inflammatory and antioxidant effects of CGA isomers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117942"},"PeriodicalIF":3.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142420509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digoxin and its Na+/K+-ATPase-targeted actions on cardiovascular diseases and cancer","authors":"Yulin Ren,&nbsp;Andrew T. Anderson,&nbsp;Gunnar Meyer,&nbsp;Kaitlyn M. Lauber,&nbsp;Judith C. Gallucci,&nbsp;A. Douglas Kinghorn","doi":"10.1016/j.bmc.2024.117939","DOIUrl":"10.1016/j.bmc.2024.117939","url":null,"abstract":"<div><div>Na⁺/K⁺-ATPase (NKA) is a plasma membrane ion-transporting protein involved in the generation and maintenance of Na⁺ and K⁺ gradients across the cell membrane, which can produce a driving force for the secondary transport of metabolic substrates. NKA also regulates intracellular calcium that is responsible for modulating numerous cellular processes, while it interacts with many other proteins and functions as a signal transducer, with several signaling pathways being involved. Thus, NKA has become an important target for the treatment of human diseases. Cardiac glycosides are well-known NKA inhibitors, of which (+)-digoxin or digoxin has been long used for the treatment of congestive heart failure. Also, digoxin has exhibited potential antitumor activity, by targeting directly HIF-1α, NKA, and NF-κB. Thus, the function of NKA in human cardiovascular diseases and cancer and the therapeutic effects of digoxin on these diseases are summarized in the present review, with the correlations among digoxin, NKA, cardiovascular diseases, and cancer being discussed. Presented herein are also the antitumor potential of monosaccharide cardiac glycoside analogues of digoxin, including (−)-cryptanoside A, (−)-oleandrin, (−)-ouabain, and (+)-strebloside. It is hoped that this contribution will provide some helpful information for the design and discovery of new cardiac glycoside-type therapeutic agents for the treatment of cardiovascular diseases and cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117939"},"PeriodicalIF":3.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142420320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA","authors":"Zhikun Liu ,&nbsp;Shining Mao ,&nbsp;Lumei Dai ,&nbsp;Rizhen Huang ,&nbsp;Weiwei Hu ,&nbsp;Chunhao Yu ,&nbsp;Yong Yang ,&nbsp;Guoxiu Cao ,&nbsp;Xiaochao Huang","doi":"10.1016/j.bmc.2024.117936","DOIUrl":"10.1016/j.bmc.2024.117936","url":null,"abstract":"<div><div>PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds <strong>13a</strong>–<strong>14c</strong> obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound <strong>13b</strong> showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, <strong>13b</strong> displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), <strong>11b</strong> (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that <strong>13b</strong> may serve as a potential candidate for BRCA wild-type TNBC.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"113 ","pages":"Article 117936"},"PeriodicalIF":3.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of arylpropylamine derivatives as potential multi-target antidepressants","authors":"Quxiang Li ,&nbsp;Qiang Guo ,&nbsp;Lili Ren ,&nbsp;Song Zhao ,&nbsp;Junyong Luo ,&nbsp;Yi Zhang ,&nbsp;Wenchao Zhou ,&nbsp;Xiangqing Xu ,&nbsp;Guoguang Chen","doi":"10.1016/j.bmc.2024.117935","DOIUrl":"10.1016/j.bmc.2024.117935","url":null,"abstract":"<div><div>In this study, a series of novel arylpropylamine derivatives were designed, synthesized and evaluated as potential multi-target antidepressants. Among them, compound <strong>(<em>R</em>)-13j</strong> displayed unique pharmacological features, exhibiting excellent inhibitory potency against serotonin and noradrenaline transporters (SERT/NET) and high affinity for 5-HT_2A/_2C receptor, and showing low affinity for histamine H₁, adrenergic α₁ receptors and hERG channels (to reduce QT interval prolongation). Molecular docking studies provided a rational binding model of <strong>(<em>R</em>)-13j</strong> in complex with SERT and 5-HT_2A/2C receptor. In animal models, compound <strong>(<em>R</em>)-13j</strong> dose-dependently reduced the immobility time in the tail suspension test (TST) and the forced swimming test (FST) in mice, with higher efficacy when compared to duloxetine, and showed no stimulatory effect on the locomotor activity. Moreover, compound <strong>(<em>R</em>)-13j</strong> significantly shortened the immobility time in the ACTH-induced rat model of treatment-resistant depression (TRD). Furthermore, compound <strong>(<em>R</em>)-13j</strong> also exhibited a higher threshold for acute toxicity than duloxetine. In addition, compound <strong>(<em>R</em>)-13j</strong> possessed a favorable pharmacokinetic profile in mice. Taken together, compound <strong>(<em>R</em>)-13j</strong> may constitute a novel class of drugs for the treatment of depression.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117935"},"PeriodicalIF":3.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and antitumor effects of lupeol quaternary phosphonium salt derivatives","authors":"Zongxing Chen ,&nbsp;Ran Luo ,&nbsp;Tianci Xu ,&nbsp;Lu Wang ,&nbsp;Siqi Deng ,&nbsp;Jiale Wu ,&nbsp;Haijun Wang ,&nbsp;Yu Lin ,&nbsp;Ming Bu","doi":"10.1016/j.bmc.2024.117934","DOIUrl":"10.1016/j.bmc.2024.117934","url":null,"abstract":"<div><div>Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound <strong>6c</strong> was found to have an IC₅₀ value of 1.83 μM and a selectivity index of 21.02 (IC₅₀MRC-5/IC₅₀A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound <strong>14f</strong> was found to have an IC₅₀ value of 1.36 μM and a selectivity index of 15.60 (IC₅₀MRC-5/IC₅₀A549) against A549 cells. We further evaluated the bioactivity of compounds <strong>6c</strong> and <strong>14f</strong> and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound <strong>14f</strong> showed stronger bioactivity than compound <strong>6c</strong>. We then selected compound <strong>14f</strong> for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound <strong>14f</strong> was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and <strong>14f</strong> was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound <strong>14f</strong> has great potential in the development of antitumor drugs targeting mitochondria.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"113 ","pages":"Article 117934"},"PeriodicalIF":3.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbonic anhydrases: Moiety appended derivatives, medicinal and pharmacological implications","authors":"Aashish Jaitak,&nbsp;Khushi Kumari,&nbsp;Sanjay Kounder,&nbsp;Vikramdeep Monga","doi":"10.1016/j.bmc.2024.117933","DOIUrl":"10.1016/j.bmc.2024.117933","url":null,"abstract":"<div><div>In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure–activity relationships, biological evaluation, and <em>in silico</em> studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117933"},"PeriodicalIF":3.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropanoic acids as selective and effective carboxylesterase inhibitors with powerful antioxidant potential","authors":"Yanina V. Burgart ,&nbsp;Galina F. Makhaeva ,&nbsp;Olga G. Khudina ,&nbsp;Olga P. Krasnykh ,&nbsp;Nadezhda V. Kovaleva ,&nbsp;Natalia A. Elkina ,&nbsp;Natalia P. Boltneva ,&nbsp;Elena V. Rudakova ,&nbsp;Sofya V. Lushchekina ,&nbsp;Evgeny V. Shchegolkov ,&nbsp;Galina A. Triandafilova ,&nbsp;Ksenia O. Malysheva ,&nbsp;Olga G. Serebryakova ,&nbsp;Sophia S. Borisevich ,&nbsp;Margarita G. Ilyina ,&nbsp;Ekaterina F. Zhilina ,&nbsp;Victor I. Saloutin ,&nbsp;Valery N. Charushin ,&nbsp;Rudy J. Richardson","doi":"10.1016/j.bmc.2024.117938","DOIUrl":"10.1016/j.bmc.2024.117938","url":null,"abstract":"<div><div>A series of 2-arylhydrazinylidene-3-oxo acids (AHOAs) was prepared by dealkylation of alkyl-2-arylhydrazinylidene-3-oxo-3-alkanoates with AlBr₃. Using X-Ray, NMR spectroscopy, and quantum mechanical calculations (QM), the existence of AHOAs in a thermodynamically favorable Z-form stabilized by two intramolecular H-bonds was established. All AHOAs had acceptable ADME parameters. The esterase profile study showed that polyfluoroalkyl-AHOAs were effective and selective carboxylesterase (CES) inhibitors, while they were inactive against acetyl- and butyrylcholinesterase. In agreement with molecular docking, the most effective CES inhibitors (IC₅₀ as low as 42 nM) were compounds bearing long polyfluoroalkyl substituents. The acids were also active against hCES1 and hCES2, and CF₃-containing acids possessed selectivity against hCES2. Non-fluorinated acids did not inhibit CES, but they exhibited potent antioxidant capability. AHOAs having unsubstituted phenyl or electron-donating groups in the arylhydrazinylidene moiety displayed high primary antioxidant activity in the ABTS, FRAP, and ORAC tests, which did not depend on the substituent in the acyl fragment in the ABTS and ORAC assays. The radical-scavenging mechanism of AHOAs was investigated using QM calculations, showing a preference for cleavage of N<img>H rather than O<img>H bonds. For the lead antioxidants, 4-methoxysubstituted AHOAs, protective effects on erythrocyte membranes in AAPH-induced oxidative stress conditions were shown, including membrane stabilizing activity, inhibition of AAPH-induced lipid peroxidation of erythrocyte membranes, and Fe(II)-chelating ability. Thus, a new class of potent and selective CES inhibitors with powerful antioxidant potential has been developed as promising co-drugs capable of regulating the metabolism of esterified drugs and scavenging reactive radicals that form during Phase I biotransformation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117938"},"PeriodicalIF":3.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design, synthesis, and biophysical characterization of a peptidic MDM2-MDM4 interaction inhibitor","authors":"Marco Ballarotto ,&nbsp;Elisa Bianconi ,&nbsp;Sonia Valentini ,&nbsp;Andrea Temperini ,&nbsp;Fabiola Moretti ,&nbsp;Antonio Macchiarulo","doi":"10.1016/j.bmc.2024.117937","DOIUrl":"10.1016/j.bmc.2024.117937","url":null,"abstract":"<div><div>In recent years, the restoration of p53 physiological functions has become an attractive therapeutic approach to develop novel and efficacious cancer therapies. Among other mechanisms, the oncosuppressor protein p53 is functionally regulated by MDM2 through its E3 ligase function. MDM2 promotes p53 ubiquitination and degradation following homodimerization or heterodimerization with MDM4. Recently, we discovered Pep3 (<strong>1</strong>, Pellegrino <em>et al.</em>, 2015), a novel peptidic inhibitor of MDM2 dimerization able to restore p53 oncosuppressive functions both <em>in vitro</em> and <em>in vivo</em>. In this work, we were able to identify the key interactions between peptide <strong>1</strong> and MDM2 RING domain and to design peptide <strong>2</strong>, a truncated version of <strong>1</strong> that is still able to bind MDM2. Integrating both computational and biophysical techniques, we show that peptide <strong>2</strong> maintains the conserved peptide <strong>1</strong>-MDM2 interactions and is still able to bind to full-length MDM2.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"113 ","pages":"Article 117937"},"PeriodicalIF":3.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of a potent and selective dual JAK1/TYK2 inhibitor","authors":"Oscar Mammoliti ,&nbsp;Christel Menet ,&nbsp;Céline Cottereaux ,&nbsp;Javier Blanc ,&nbsp;Ann De Blieck ,&nbsp;Ghjuvanni Coti ,&nbsp;Raphaël Geney ,&nbsp;Line Oste ,&nbsp;Koen Ostyn ,&nbsp;Adeline Palisse ,&nbsp;Evelyne Quinton ,&nbsp;Benoit Schmitt ,&nbsp;Monica Borgonovi ,&nbsp;Isabelle Parent ,&nbsp;Catherine Jagerschmidt ,&nbsp;Steve De Vos ,&nbsp;Béatrice Vayssiere ,&nbsp;Miriam López-Ramos ,&nbsp;Kenji Shoji ,&nbsp;Reginald Brys ,&nbsp;Caroline Joannesse","doi":"10.1016/j.bmc.2024.117932","DOIUrl":"10.1016/j.bmc.2024.117932","url":null,"abstract":"<div><div>Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T_H1 and T_H17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23-induced psoriasis-like inflammation mouse model.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117932"},"PeriodicalIF":3.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}