A substantial proportion of patients with prostate cancer (PCa) develop treatment resistance or mortality after androgen deprivation therapy (ADT). Current methods for identifying and locating recurrent lesions using prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging, which relies on androgen levels, often result in diagnostic delays. Therefore, the development of an androgen-independent radiotracer is critical for the early identification of recurrent lesions. The neurotensin receptor 1 (NTSR1) is highly expressed in androgen-independent PCa lesions. Here, we synthesized a bispecific ligand targeting PSMA and NTSR1 by solid-phase peptide synthesis and formulated a 68Ga-labelled bispecific radiotracer, ([68Ga]Ga-NT-PSMA). This radiotracer exhibited a high radiochemical yield (71.27% ± 1.58%) and demonstrated an affinity for NTSR1 (39.32 ± 2.98 nM) and PSMA (63.47 ± 5.14 nM) in vitro. Small animal PET imaging showed comparable uptake of [68Ga]Ga-NT-PSMA and the monomeric radiotracer [68Ga]Ga-DOTA-NT20.3 in mice bearing androgen-independent PC3 (3.64 ± 0.49 %ID/g vs. 5.60 ± 1.42 %ID/g, nonsignificant [ns]) and DU145 tumors (2.49 ± 0.20 %ID/g vs. 2.34 ± 0.18 %ID/g, ns) at 90 min post-injection. In androgen-dependent 22Rv1 xenografts, [68Ga]Ga-NT-PSMA uptake was lower (1.94 ± 0.29 %ID/g) than [68Ga]Ga-PSMA-11 (3.94 ± 0.26 %ID/g, P < 0.001). Nevertheless, [68Ga]Ga-NT-PSMA effectively imaged all three xenograft types with high contrast, an achievement not possible with monomeric radiotracers alone. These results indicate that imaging with [68Ga]Ga-NT-PSMA is independent of the androgen dependence of the model, highlighting its potential as a promising nuclear medicine diagnostic tool for the early identification and localization of castration-resistant PCa lesions.
{"title":"A novel androgen-independent radiotracer with dual targeting of NTSR1 and PSMA for PET/CT imaging of prostate cancer","authors":"Qiong Wang, Zhongjing Li, Yong Huang, Chengze Li, Yiluo Li, Yi Peng, Zonghai Sheng, Ying Liang","doi":"10.1016/j.ejmech.2024.117050","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117050","url":null,"abstract":"A substantial proportion of patients with prostate cancer (PCa) develop treatment resistance or mortality after androgen deprivation therapy (ADT). Current methods for identifying and locating recurrent lesions using prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging, which relies on androgen levels, often result in diagnostic delays. Therefore, the development of an androgen-independent radiotracer is critical for the early identification of recurrent lesions. The neurotensin receptor 1 (NTSR1) is highly expressed in androgen-independent PCa lesions. Here, we synthesized a bispecific ligand targeting PSMA and NTSR1 by solid-phase peptide synthesis and formulated a <sup>68</sup>Ga-labelled bispecific radiotracer, ([<sup>68</sup>Ga]Ga-NT-PSMA). This radiotracer exhibited a high radiochemical yield (71.27% ± 1.58%) and demonstrated an affinity for NTSR1 (39.32 ± 2.98 nM) and PSMA (63.47 ± 5.14 nM) <em>in vitro</em>. Small animal PET imaging showed comparable uptake of [<sup>68</sup>Ga]Ga-NT-PSMA and the monomeric radiotracer [<sup>68</sup>Ga]Ga-DOTA-NT20.3 in mice bearing androgen-independent PC3 (3.64 ± 0.49 %ID/g vs. 5.60 ± 1.42 %ID/g, nonsignificant [ns]) and DU145 tumors (2.49 ± 0.20 %ID/g vs. 2.34 ± 0.18 %ID/g, ns) at 90 min post-injection. In androgen-dependent 22Rv1 xenografts, [<sup>68</sup>Ga]Ga-NT-PSMA uptake was lower (1.94 ± 0.29 %ID/g) than [<sup>68</sup>Ga]Ga-PSMA-11 (3.94 ± 0.26 %ID/g, <em>P</em> < 0.001). Nevertheless, [<sup>68</sup>Ga]Ga-NT-PSMA effectively imaged all three xenograft types with high contrast, an achievement not possible with monomeric radiotracers alone. These results indicate that imaging with [<sup>68</sup>Ga]Ga-NT-PSMA is independent of the androgen dependence of the model, highlighting its potential as a promising nuclear medicine diagnostic tool for the early identification and localization of castration-resistant PCa lesions.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.ejmech.2024.117054
Ke Xu, Feng Li, Liang Xiong, Yinping Guo, Jian Zhang, Yuyang Wang, Shanmian Ji, Shengyong Yang, Linli Li
AlkB homolog 2 (ALKBH2) is a Fe (II) and 2-oxoglutarate (2OG)-dependent DNA demethylase. It has been reported to be highly expressed in many cancers including glioblastoma (GBM) and affected disease progression by regulating gene expression. Small molecule inhibitors of ALKBH2 might be used as disease intervention reagents or chemical tools for bio-functional studies of ALKBH2, but currently no potent and selective ALKBH2 inhibitors are reported. We herein disclose a new potent and selective ALKBH2 inhibitor (AH2-15c), which showed an IC50 value of 0.031±0.001 μM in a fluorescence polarization (FP) assay and exhibited more than 200-fold selectivity towards ALKBH2 versus other AlkB subfamily members. Since AH2-15c showed very low cellular activity due to its poor cell membrane permeability originating from the carboxyl group, we investigated the un-hydrolyzed counterpart AH2-14c. AH2-14c could directly bind to ALKBH2 and increase the abundance of DNA N3-methylcytosine (3meC) modifications in GBM U87 cells, with a superior effect to AH2-15c. In addition, AH2-14c exhibited much better activities of anti-viability, anti-proliferation and anti-migration against U87 cells. Collectively, we discovered the first potent and selective ALKBH2 inhibitor, which could be taken as a foundation for future drug development and mechanism of action studies.
{"title":"Discovery and structure-activity relationship study of nicotinamide derivatives as DNA demethylase ALKBH2 inhibitors","authors":"Ke Xu, Feng Li, Liang Xiong, Yinping Guo, Jian Zhang, Yuyang Wang, Shanmian Ji, Shengyong Yang, Linli Li","doi":"10.1016/j.ejmech.2024.117054","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117054","url":null,"abstract":"AlkB homolog 2 (ALKBH2) is a Fe (II) and 2-oxoglutarate (2OG)-dependent DNA demethylase. It has been reported to be highly expressed in many cancers including glioblastoma (GBM) and affected disease progression by regulating gene expression. Small molecule inhibitors of ALKBH2 might be used as disease intervention reagents or chemical tools for bio-functional studies of ALKBH2, but currently no potent and selective ALKBH2 inhibitors are reported. We herein disclose a new potent and selective ALKBH2 inhibitor (<strong>AH2-15c</strong>), which showed an IC<sub>50</sub> value of 0.031±0.001 μM in a fluorescence polarization (FP) assay and exhibited more than 200-fold selectivity towards ALKBH2 versus other AlkB subfamily members. Since <strong>AH2-15c</strong> showed very low cellular activity due to its poor cell membrane permeability originating from the carboxyl group, we investigated the un-hydrolyzed counterpart <strong>AH2-14c. AH2-14c</strong> could directly bind to ALKBH2 and increase the abundance of DNA <em>N</em><sup>3</sup>-methylcytosine (3meC) modifications in GBM U87 cells, with a superior effect to <strong>AH2-15c</strong>. In addition, <strong>AH2-14c</strong> exhibited much better activities of anti-viability, anti-proliferation and anti-migration against U87 cells. Collectively, we discovered the first potent and selective ALKBH2 inhibitor, which could be taken as a foundation for future drug development and mechanism of action studies.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ejmech.2024.117061
Yunpeng Yi , Jiaming Zhang , Shuqian Lin , Haiting Wang , Guiyu Li , Shifa Yang , Ruofeng Shang , Rongling Zhang , Fei Li
Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated in vitro and in vivo antibacterial activities. Several compounds showed potent activity against MRSA and Staphylococcus aureus with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds a4 and b4 showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. In vivo, compound a4 showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound a4 binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound a4, with its enhanced antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections.
{"title":"Design, synthesis, and biological evaluation of novel pleuromutilin derivatives with methicillin-resistant Staphylococcus aureus -targeting phenol linker groups","authors":"Yunpeng Yi , Jiaming Zhang , Shuqian Lin , Haiting Wang , Guiyu Li , Shifa Yang , Ruofeng Shang , Rongling Zhang , Fei Li","doi":"10.1016/j.ejmech.2024.117061","DOIUrl":"10.1016/j.ejmech.2024.117061","url":null,"abstract":"<div><div>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) remains a significant global health threat, necessitating the development of new therapeutic agents. Pleuromutilin derivatives offer a promising solution due to their potent antibacterial activity, particularly against Gram-positive bacteria such as MRSA. In this study, we synthesized a series of pleuromutilin derivatives with phenol linker containing C14 side chains and evaluated <em>in vitro</em> and <em>in vivo</em> antibacterial activities. Several compounds showed potent activity against MRSA and <em>Staphylococcus aureus</em> with minimal inhibitory concentrations (MICs) as low as 0.03125 μg/mL. In particular, compounds <strong>a4</strong> and <strong>b4</strong> showed rapid bactericidal activity, significantly reducing MRSA loads in time-kill kinetics and exhibiting slower resistance development compared to tiamulin. <em>In vivo</em>, compound <strong>a4</strong> showed superior efficacy in reducing MRSA-induced lung damage in a mouse model at a lower effective dose (ED50 = 6.48 mg/kg) compared to tiamulin (ED50 = 11.38 mg/kg). Molecular docking and molecular dynamics studies also showed that compound <strong>a4</strong> binds strongly to the ribosomal peptidyl transferase center (PTC), a key target for pleuromutilin derivatives. These results suggest that compound <strong>a4</strong>, with its enhanced antibacterial activity and low resistance potential, is a promising candidate for further development as an effective treatment for MRSA infections.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117061"},"PeriodicalIF":6.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TRP channels are essential for detecting variations in external temperature and are ubiquitously expressed in both the peripheral and central nervous systems as integral channel proteins. They primarily mediate a range of sensory responses, including thermal sensations, nociception, mechanosensation, vision, and gustation, thus playing a critical role in regulating various physiological functions. In colder climates, individuals often experience pain associated with low temperatures, leading to significant discomfort. Within the TRP channel family, TRPM8 and TRPA1 ion channels serve as the primary sensors for cold temperature fluctuations and are integral to both cold nociception and neuropathic pain pathways. Recent advancements in the biosynthesis of inhibitors targeting TRPM8 and TRPA1 have prompted the need for a comprehensive review of their structural characteristics, biological activities, biosynthetic pathways, and chemical synthesis. This paper aims to delineate the distinct roles of TRPM8 and TRPA1 in pain perception, elucidate their respective protein structures, and compile various combinations of TRPM8 and TRPA1 antagonists and agonists. The discussion encompasses their chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, with a particular focus on the conformational relationships between antagonists and the channels. This review seeks to provide in-depth insights into pharmacological strategies for managing pain associated with TRPM8 and TRPA1 activation and will pave the way for future investigations into pharmacotherapeutic approaches for alleviating cold-induced pain.
{"title":"TRPM8 and TRPA1 Ideal Targets for Treating Cold-Induced Pain","authors":"Yiming Qi, Hao Gong, Zixian Shen, Limeng Wu, Zonghe Xu, Nuo Shi, Kexin Lin, Meng Tian, Zihua Xu, Xiang Li, Qingchun Zhao","doi":"10.1016/j.ejmech.2024.117043","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117043","url":null,"abstract":"TRP channels are essential for detecting variations in external temperature and are ubiquitously expressed in both the peripheral and central nervous systems as integral channel proteins. They primarily mediate a range of sensory responses, including thermal sensations, nociception, mechanosensation, vision, and gustation, thus playing a critical role in regulating various physiological functions. In colder climates, individuals often experience pain associated with low temperatures, leading to significant discomfort. Within the TRP channel family, TRPM8 and TRPA1 ion channels serve as the primary sensors for cold temperature fluctuations and are integral to both cold nociception and neuropathic pain pathways. Recent advancements in the biosynthesis of inhibitors targeting TRPM8 and TRPA1 have prompted the need for a comprehensive review of their structural characteristics, biological activities, biosynthetic pathways, and chemical synthesis. This paper aims to delineate the distinct roles of TRPM8 and TRPA1 in pain perception, elucidate their respective protein structures, and compile various combinations of TRPM8 and TRPA1 antagonists and agonists. The discussion encompasses their chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, with a particular focus on the conformational relationships between antagonists and the channels. This review seeks to provide in-depth insights into pharmacological strategies for managing pain associated with TRPM8 and TRPA1 activation and will pave the way for future investigations into pharmacotherapeutic approaches for alleviating cold-induced pain.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"80 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ejmech.2024.117056
Bin Rong, Xiaochun Dong, Weili Zhao
A series of integrin αvβ3 targeting BODIPY-RGD conjugate were designed and synthesized. Their in vitro and in vivo fluorescence imaging behaviors were investigated. The small molecule compound was designed as an optical imaging near-infrared fluorescent dye which was combined RGD peptide with the meso-amide BODIPYs using succinic moiety as a spacer. The construction alleviated the traditional BODIPY problems including poor water solubility, aggregate caused quench (ACQ) effect, low biocompatibility, etc. In cellular research, BDP-RGD-2 showed rapid, selective uptake in 3 highly expressing integrin αvβ3 cell lines MDA-MB-231, A549, U87MG at different extent rather than an integrin αvβ3 low level expression cell MCF-7. In animal study, fluorescence imaging of U87MG model targeted by BDP-RGD-2 displayed a highest tumor uptake level and T/N ratio up to 6 h after tail-intravenous injection, which demonstrated BDP-RGD-2 was a promising probe for tracing integrin αvβ3 overexpressing tumors.
{"title":"Synthesis and evaluation of a novel BODIPY fluorescent probe targeting integrin αvβ3 for cancer diagnosis","authors":"Bin Rong, Xiaochun Dong, Weili Zhao","doi":"10.1016/j.ejmech.2024.117056","DOIUrl":"10.1016/j.ejmech.2024.117056","url":null,"abstract":"<div><div>A series of integrin α<sub>v</sub>β<sub>3</sub> targeting BODIPY-RGD conjugate were designed and synthesized. Their <em>in vitro</em> and <em>in vivo</em> fluorescence imaging behaviors were investigated. The small molecule compound was designed as an optical imaging near-infrared fluorescent dye which was combined RGD peptide with the <em>meso</em>-amide BODIPYs using succinic moiety as a spacer. The construction alleviated the traditional BODIPY problems including poor water solubility, aggregate caused quench (ACQ) effect, low biocompatibility, etc. In cellular research, <strong>BDP-RGD-2</strong> showed rapid, selective uptake in 3 highly expressing integrin α<sub>v</sub>β<sub>3</sub> cell lines MDA-MB-231, A549, U87MG at different extent rather than an integrin α<sub>v</sub>β<sub>3</sub> low level expression cell MCF-7. In animal study, fluorescence imaging of U87MG model targeted by <strong>BDP-RGD-2</strong> displayed a highest tumor uptake level and T/N ratio up to 6 h after tail-intravenous injection, which demonstrated <strong>BDP-RGD-2</strong> was a promising probe for tracing integrin α<sub>v</sub>β<sub>3</sub> overexpressing tumors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117056"},"PeriodicalIF":6.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ejmech.2024.117053
Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li
Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (C8) inhibited PTP1B noncompetitively with an IC50 value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS db/db mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.
{"title":"Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives","authors":"Chenxia Gao, Wenpeng Hu, Feng Xu, Yuxi Lin, Jiashu Chen, Dayong Shi, Pan Xing, Jiqiang Zhu, Xiangqian Li","doi":"10.1016/j.ejmech.2024.117053","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117053","url":null,"abstract":"Development of allosteric inhibitors may be a viable strategy to discover hypoglycemic drugs targeting PTP1B. Allosteric inhibitors occupying the BB site that is a hydrophobic pocket restrict the WPD loop in an open conformation, preventing the physiological dephosphorylation reaction. Toward the BB site, sixty bromocatechol-chalcone derivatives were designed and synthesized as allosteric inhibitors of PTP1B against diabetes mellitus. The most potent compound LXQ-87 (<strong>C8</strong>) inhibited PTP1B noncompetitively with an IC<sub>50</sub> value of 1.061±0.202 μM. Oral administration of LXQ-87 reduces the fasting blood glucose level and improves glucose tolerance and dyslipidemia in BKS <em>db</em>/<em>db</em> mice suffering from T2DM. LXQ-87 alleviates insulin resistance and promotes cellular glucose uptake by directly binding to intracellular PTP1B.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"216 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ejmech.2024.117048
Hend Khalifa, Ahmed K. ElHady, Ting Liu, Walid A.M. Elgaher, Odile Filhol, Claude Cochet, Ashraf H. Abadi, Mostafa M. Hamed, Mohammad Abdel-Halim, Matthias Engel
CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-d]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC50 values in the nanomolar range. Compound 10b demonstrated the most balanced activity profile with a cell-free IC50 value of 36.7 nM and a notable cellular activity with a GI50 of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. 10b displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, 10b inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range.
{"title":"Discovery of a novel, selective CK2 inhibitor class with an unusual basic scaffold","authors":"Hend Khalifa, Ahmed K. ElHady, Ting Liu, Walid A.M. Elgaher, Odile Filhol, Claude Cochet, Ashraf H. Abadi, Mostafa M. Hamed, Mohammad Abdel-Halim, Matthias Engel","doi":"10.1016/j.ejmech.2024.117048","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117048","url":null,"abstract":"CK2 is a Ser/Thr-protein kinase playing a crucial role in promoting cell growth and survival, hence it is considered a promising target for anti-cancer drugs. However, many previously reported CK2 inhibitors lack selectivity. In search of novel scaffolds for selective CK2 inhibition, we identified a dihydropyrido-thieno[2,3-<em>d</em>]pyrimidine derivative displaying submicromolar inhibitory activity against CK2α. This scaffold captured our interest because of the basic secondary amine, a rather unusual motif for CK2 inhibitors. Our optimization strategy comprised the incorporation of a 4-piperazinyl moiety as a linker group and introduction of varying substituents on the pendant phenyl ring. All resulting compounds exhibited potent CK2α inhibition, with IC<sub>50</sub> values in the nanomolar range. Compound <strong>10b</strong> demonstrated the most balanced activity profile with a cell-free IC<sub>50</sub> value of 36.7 nM and a notable cellular activity with a GI<sub>50</sub> of 7.3 μM and 7.5 μM against 786-O renal cell carcinoma and U937 lymphoma cells, respectively. <strong>10b</strong> displayed excellent selectivity when screened against a challenging kinase selectivity profiling panel. Moreover, <strong>10b</strong> inhibited CK2 in the cells, albeit less potently than CX-4945, but induced cell death more strongly than CX-4945. Altogether, we have identified a novel CK2 inhibitory scaffold with drug-like physicochemical properties in a favorable basic pKa range.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"33 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.ejmech.2024.117051
Bo Feng, Hui Yu, Xu Dong, Alejandro Díaz-Holguín, Huabin Hu
The extensive bioactivity data available in public databases, such as ChEMBL, has facilitated in-depth structure-activity relationship (SAR) analyses, which are essential for understanding the impact of molecular modifications on biological activity. A central strategy in SAR analysis is the assessment of molecular similarity. Several approaches preferred by medicinal chemists have been developed to efficiently capture structurally related compounds on a large scale. Represented as a popular molecular editing strategy in hit-to-lead and lead optimization processes, we previously introduced four types of single-atom modifications (SAMs) and conducted a systematic analysis of their application in compound design. In this study, we expanded the analysis to cover 10 common SAMs, including carbon-nitrogen (N↔C), O↔C, N↔O, S↔O, as well as simpler modifications such as OH↔H, CH3↔H, and halogen-hydrogen (F, Cl, Br, I ↔ H) exchanges. Leveraging high-confidence bioactivity data from ChEMBL (version 34), we assembled the largest dataset of SAM pairs to date, comprising 374,979 pairs. Following an evaluation of the frequency of these SAM types in medicinal chemistry, we focused on SAM-induced activity cliffs (ACs), yielding over 7,400 ACs involving SAMs, substantially expanding the current knowledgebase of ACs associated with single-atom changes. Furthermore, structural analysis of these ACs, supported by experimental data, provides critical insights into the role of single-atom modifications in modulating compound activity, offering practical guidance for the structure-based optimization of molecular properties in drug development. As a result, we are providing open access to all identified ACs along with their associated structural information.
ChEMBL 等公共数据库提供的大量生物活性数据有助于进行深入的结构-活性关系（SAR）分析，这对于了解分子修饰对生物活性的影响至关重要。SAR 分析的核心策略是评估分子相似性。目前已开发出几种药物化学家偏爱的方法，可有效地大规模捕获结构相关的化合物。单原子修饰（SAMs）作为一种流行的分子编辑策略，被广泛应用于 "命中先导"（hit-to-lead）和 "先导优化"（lead optimization）过程中，我们之前介绍了四种单原子修饰（SAMs），并对其在化合物设计中的应用进行了系统分析。在本研究中，我们扩大了分析范围，涵盖了 10 种常见的单原子修饰，包括碳-氮（N↔C）、O↔C、N↔O、S↔O 以及更简单的修饰，如 OH↔H、CH3↔H 和卤素-氢（F、Cl、Br、I ↔ H）交换。利用来自 ChEMBL（34 版）的高置信度生物活性数据，我们建立了迄今为止最大的 SAM 对数据集，包括 374,979 对。在对这些 SAM 类型在药物化学中的出现频率进行评估后，我们重点研究了 SAM 诱导的活性悬崖（AC），得出了 7,400 多个涉及 SAM 的 AC，大大扩展了目前与单原子变化相关的 AC 的知识库。此外，在实验数据的支持下，这些 AC 的结构分析为了解单原子修饰在调节化合物活性方面的作用提供了重要见解，为在药物开发过程中基于结构优化分子特性提供了实用指导。因此，我们将开放所有已鉴定的 ACs 及其相关结构信息。
{"title":"Identification of bioactive compounds with popular single-atom modifications: comprehensive analysis and implications for compound design","authors":"Bo Feng, Hui Yu, Xu Dong, Alejandro Díaz-Holguín, Huabin Hu","doi":"10.1016/j.ejmech.2024.117051","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117051","url":null,"abstract":"The extensive bioactivity data available in public databases, such as ChEMBL, has facilitated in-depth structure-activity relationship (SAR) analyses, which are essential for understanding the impact of molecular modifications on biological activity. A central strategy in SAR analysis is the assessment of molecular similarity. Several approaches preferred by medicinal chemists have been developed to efficiently capture structurally related compounds on a large scale. Represented as a popular molecular editing strategy in hit-to-lead and lead optimization processes, we previously introduced four types of single-atom modifications (SAMs) and conducted a systematic analysis of their application in compound design. In this study, we expanded the analysis to cover 10 common SAMs, including carbon-nitrogen (N↔C), O↔C, N↔O, S↔O, as well as simpler modifications such as OH↔H, CH<sub>3</sub>↔H, and halogen-hydrogen (F, Cl, Br, I ↔ H) exchanges. Leveraging high-confidence bioactivity data from ChEMBL (version 34), we assembled the largest dataset of SAM pairs to date, comprising 374,979 pairs. Following an evaluation of the frequency of these SAM types in medicinal chemistry, we focused on SAM-induced activity cliffs (ACs), yielding over 7,400 ACs involving SAMs, substantially expanding the current knowledgebase of ACs associated with single-atom changes. Furthermore, structural analysis of these ACs, supported by experimental data, provides critical insights into the role of single-atom modifications in modulating compound activity, offering practical guidance for the structure-based optimization of molecular properties in drug development. As a result, we are providing open access to all identified ACs along with their associated structural information.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117014
Lu Tang, Xingyu Chang, Jing Shi, Zhenfan Wen, Chunyang Bi, Wukun Liu
Platinum-based drugs are a mainstay in chemotherapy, with traditional forms exerting their work directly on DNA. In recent years, it has been observed that platinum complexes have the potential to induce immunogenic cell death (ICD) and effectively trigger antitumor immune responses. Herein, to obtain novel platinum complexes with chemo-immunological properties, a series of Pt(ΙΙ)-N-heterocyclic carbene (Pt(ΙΙ)-NHC) complexes derived from 4,5-diarylimidazoles were synthesized. Among them, the dominant complex 3f was proved to exhibit better anti-liver cancer capacity compared to cisplatin and oxaliplatin. Complex 3f showed the ability to cause DNA damage by binding to DNA. In addition, it triggered intracellular reactive oxygen species (ROS) generation, affected the function of mitochondria, and blocked cells in G0/G1 phase, ultimately induced apoptosis in liver cancer cells. Furthermore, complex 3f activated endoplasmic reticulum stress (ERS) which promoted the release of damage-associated molecular patterns (DAMPs), induced ICD and dendritic cells (DCs) maturation. Interestingly, complex 3f also upregulated PD-L1, consequently converted "cold tumors" into "hot tumors". Overall, complex 3f had the potential to be regarded as a promising chemoimmunotherapy for the treatment of liver cancer.
{"title":"More than just DNA damage: Pt(ΙΙ)-NHC complexes derived from 4,5-diarylimidazoles augment immunogenic cell death","authors":"Lu Tang, Xingyu Chang, Jing Shi, Zhenfan Wen, Chunyang Bi, Wukun Liu","doi":"10.1016/j.ejmech.2024.117014","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117014","url":null,"abstract":"Platinum-based drugs are a mainstay in chemotherapy, with traditional forms exerting their work directly on DNA. In recent years, it has been observed that platinum complexes have the potential to induce immunogenic cell death (ICD) and effectively trigger antitumor immune responses. Herein, to obtain novel platinum complexes with chemo-immunological properties, a series of Pt(ΙΙ)-<em>N</em>-heterocyclic carbene (Pt(ΙΙ)-NHC) complexes derived from 4,5-diarylimidazoles were synthesized. Among them, the dominant complex <strong>3f</strong> was proved to exhibit better anti-liver cancer capacity compared to cisplatin and oxaliplatin. Complex <strong>3f</strong> showed the ability to cause DNA damage by binding to DNA. In addition, it triggered intracellular reactive oxygen species (ROS) generation, affected the function of mitochondria, and blocked cells in G0/G1 phase, ultimately induced apoptosis in liver cancer cells. Furthermore, complex <strong>3f</strong> activated endoplasmic reticulum stress (ERS) which promoted the release of damage-associated molecular patterns (DAMPs), induced ICD and dendritic cells (DCs) maturation. Interestingly, complex <strong>3f</strong> also upregulated PD-L1, consequently converted \"cold tumors\" into \"hot tumors\". Overall, complex <strong>3f</strong> had the potential to be regarded as a promising chemoimmunotherapy for the treatment of liver cancer.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117026
Florine TOULOTTE, Mathilde COEVOET, Maxime LIBERELLE, Fabrice BAILLY, Benjamin ZAGIEL, Muriel GELIN, Frédéric ALLEMAND, Patrick FOURQUET, Patricia MELNYK, G.U.I.C.H.O.U. Jean-François, Philippe COTELLE
The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.
{"title":"TOWARDS THE DESIGN OF LIGANDS OF THE INTERNAL POCKET TEADS C-TERMINAL DOMAIN","authors":"Florine TOULOTTE, Mathilde COEVOET, Maxime LIBERELLE, Fabrice BAILLY, Benjamin ZAGIEL, Muriel GELIN, Frédéric ALLEMAND, Patrick FOURQUET, Patricia MELNYK, G.U.I.C.H.O.U. Jean-François, Philippe COTELLE","doi":"10.1016/j.ejmech.2024.117026","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117026","url":null,"abstract":"The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"452 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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