Bioorganic & Medicinal Chemistry最新文献

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Identification and optimization of a small molecule inhibitor of the ovarian tumor protease of the Crimean-Congo hemorrhagic fever virus

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-30 DOI: 10.1016/j.bmc.2025.118093

Lorenz Beckmann , Fabian Liessmann , Maik Icker , Dominic Rieger , Phillip Schlegel , Nicole Urban , Michael Schaefer , Jens Meiler , Clara T. Schoeder , Maik Tretbar

Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne disease with fatality rates of up to 30 %. Currently, there are no vaccines or specific antivirals available. The genome of the CCHF virus (CCHFV) encodes an ovarian tumor (OTU) protease with a deubiquitinating activity that is responsible for the evasion of the innate immune response. Therefore, the inhibition of the OTU protease could provide a strategy for the treatment of CCHFV infections. In this study, we screened for small-molecule inhibitors of CCHFV OTU using a fluorescent ubiquitin rhodamine 110 assay. We identified and validated a 2-aminothiazole hit compound (IC₅₀ = 42.3 μM) followed by structure–activity relationships (SAR) studies resulting in a new inhibitor of the CCHFV OTU protease. The most active derivative is a competitive CCHFV OTU inhibitor with an IC₅₀ value of 10.7 μM. Selectivity studies revealed that the ubiquitin-specific peptidase 7 (USP7), ubiquitin C–terminal hydrolase 5 (UCHL5), OTU deubiquitinase 1 (OTUD1), and Cezanne are also inhibited by this newly developed inhibitor indicating binding to conserved regions of the ubiquitin-binding site within the deubiquitinase superfamilies. Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure–activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.

{"title":"Identification and optimization of a small molecule inhibitor of the ovarian tumor protease of the Crimean-Congo hemorrhagic fever virus","authors":"Lorenz Beckmann , Fabian Liessmann , Maik Icker , Dominic Rieger , Phillip Schlegel , Nicole Urban , Michael Schaefer , Jens Meiler , Clara T. Schoeder , Maik Tretbar","doi":"10.1016/j.bmc.2025.118093","DOIUrl":"10.1016/j.bmc.2025.118093","url":null,"abstract":"<div><div>Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne disease with fatality rates of up to 30 %. Currently, there are no vaccines or specific antivirals available. The genome of the CCHF virus (CCHFV) encodes an ovarian tumor (OTU) protease with a deubiquitinating activity that is responsible for the evasion of the innate immune response. Therefore, the inhibition of the OTU protease could provide a strategy for the treatment of CCHFV infections. In this study, we screened for small-molecule inhibitors of CCHFV OTU using a fluorescent ubiquitin rhodamine 110 assay. We identified and validated a 2-aminothiazole hit compound (IC<sub>50</sub> = 42.3 μM) followed by structure–activity relationships (SAR) studies resulting in a new inhibitor of the CCHFV OTU protease. The most active derivative is a competitive CCHFV OTU inhibitor with an IC<sub>50</sub> value of 10.7 μM. Selectivity studies revealed that the ubiquitin-specific peptidase 7 (USP7), ubiquitin C–terminal hydrolase 5 (UCHL5), OTU deubiquitinase 1 (OTUD1), and Cezanne are also inhibited by this newly developed inhibitor indicating binding to conserved regions of the ubiquitin-binding site within the deubiquitinase superfamilies. Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure–activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118093"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349441","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}

引用次数: 0

Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-30 DOI: 10.1016/j.bmc.2025.118091

Siddharth Gusain , Chandra Bhushan Mishra , Kajal Yadav , Meenakshi Sharma , Daman Saluja , Manisha Tiwari

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.

{"title":"Development of carbazole-based molecules for inhibition of mutant hSOD1 protein aggregation in Amyotrophic Lateral Sclerosis","authors":"Siddharth Gusain , Chandra Bhushan Mishra , Kajal Yadav , Meenakshi Sharma , Daman Saluja , Manisha Tiwari","doi":"10.1016/j.bmc.2025.118091","DOIUrl":"10.1016/j.bmc.2025.118091","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the loss of upper and lower motor neurons. Cu/Zn superoxide dismutase (SOD1) is one of the genes associated with the familial form of the disease (fALS). The mechanism of neuron degeneration by SOD1 is not clear, it is hypothesised that there is a toxic gain of function in the protein which leads to the downstream effects. In the present study, carbazole-based molecules have been rationally designed and synthesised as potential inhibitors of mutant hSOD1 protein aggregation. SG-9 and SG-10 prevented the aggregation of all three purified mutant hSOD1 proteins. Transmission electron microscopy and dynamic light scattering experiments also revealed that co-incubation of SG-9 and SG-10 with mutant hSOD1 protein resulted in smaller and slender fibril forming. Molecules SG-9 and SG-10 did not display toxicity and prevented Neuro-2a cells expressing hSOD1 G85R protein from its associated cytotoxicity. SG-9 and SG-10 were also able to prevent the transfected cells from apoptosis and were also able to reduce ROS levels associated with hSOD1 G85R protein aggregation significantly. Therefore, novel carbazole derivatives SG-9 and SG-10 proved to be effective inhibitors of mutant hSOD1 protein aggregation and can be further utilised as lead molecules for the amelioration of mutant hSOD1 aggregation-associated ALS.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118091"},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143287856","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}

引用次数: 0

Comparison of quaternary ammonium-based linkers for antibody–drug conjugates based on camptothecin derivatives

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-29 DOI: 10.1016/j.bmc.2025.118084

Mengyuan Ding , Ming Chen , Zhiyang Cheng , Jiyu Jin , Wei Lu , Shulei Zhu

Antibody–drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor in vitro anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (HER2-11) that combines both stability and cleavability. The optimization of the linker effectively improved the in vitro cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of HER2-11 resulted in a weaker anti-tumor activity compared to HER2-GGFG-DXd, which provides great reference value for the continued research of this type of linker in the future.

{"title":"Comparison of quaternary ammonium-based linkers for antibody–drug conjugates based on camptothecin derivatives","authors":"Mengyuan Ding , Ming Chen , Zhiyang Cheng , Jiyu Jin , Wei Lu , Shulei Zhu","doi":"10.1016/j.bmc.2025.118084","DOIUrl":"10.1016/j.bmc.2025.118084","url":null,"abstract":"<div><div>Antibody–drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor <em>in vitro</em> anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (<strong>HER2-11</strong>) that combines both stability and cleavability. The optimization of the linker effectively improved the <em>in vitro</em> cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of <strong>HER2-11</strong> resulted in a weaker anti-tumor activity compared to <strong>HER2-GGFG-DXd</strong>, which provides great reference value for the continued research of this type of linker in the future.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118084"},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077847","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}

引用次数: 0

Novel dual-targeting PROTAC degraders of GSK-3β and CDK5: A promising approach for pancreatic cancer treatment

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-29 DOI: 10.1016/j.bmc.2025.118085

Jayaprakash Neerasa, Bongsu Kim, Hunsuk Chung

Pancreatic cancer remains one of the most lethal malignancies, characterized by limited therapeutic options and poor prognoses. Here, we report the development of novel dual-targeting PROTAC (proteolysis-targeting chimera) compounds designed to concurrently degrade GSK-3β and CDK5. These bifunctional molecules were systematically designed by integrating three critical components: (1) a ligand that selectively binds GSK-3β and CDK5, (2) an E3 ligase-recruiting motif, and (3) an optimized linker to facilitate target engagement and proteasomal degradation. Our series of compounds (DBMG-01 through DBVR-PTC-02) demonstrated robust and selective target degradation in pancreatic cancer cell lines, achieving nanomolar DC₅₀ values. Among these, the lead compound DBVR-PTC-02 exhibited exceptional potency, with DC₅₀ values of 42 nM (D_max = 90 %) for GSK-3β and 48 nM (D_max = 88 %) for CDK5. DBVR-PTC-02 also displayed superior antiproliferative activity compared to single-target PROTACs and conventional kinase inhibitors, with an IC₅₀ of 1.81 ± 0.55 µM in pancreatic cancer cell viability assays. This study establishes a novel framework for dual-targeted protein degradation and highlights the therapeutic potential of DBVR-PTC-02 as a promising candidate for the treatment of pancreatic cancer.

{"title":"Novel dual-targeting PROTAC degraders of GSK-3β and CDK5: A promising approach for pancreatic cancer treatment","authors":"Jayaprakash Neerasa, Bongsu Kim, Hunsuk Chung","doi":"10.1016/j.bmc.2025.118085","DOIUrl":"10.1016/j.bmc.2025.118085","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the most lethal malignancies, characterized by limited therapeutic options and poor prognoses. Here, we report the development of novel dual-targeting PROTAC (proteolysis-targeting chimera) compounds designed to concurrently degrade GSK-3β and CDK5. These bifunctional molecules were systematically designed by integrating three critical components: (1) a ligand that selectively binds GSK-3β and CDK5, (2) an E3 ligase-recruiting motif, and (3) an optimized linker to facilitate target engagement and proteasomal degradation. Our series of compounds (DBMG-01 through DBVR-PTC-02) demonstrated robust and selective target degradation in pancreatic cancer cell lines, achieving nanomolar DC<sub>50</sub> values. Among these, the lead compound DBVR-PTC-02 exhibited exceptional potency, with DC<sub>50</sub> values of 42 nM (D<sub>max</sub> = 90 %) for GSK-3β and 48 nM (D<sub>max</sub> = 88 %) for CDK5. DBVR-PTC-02 also displayed superior antiproliferative activity compared to single-target PROTACs and conventional kinase inhibitors, with an IC<sub>50</sub> of 1.81 ± 0.55 µM in pancreatic cancer cell viability assays. This study establishes a novel framework for dual-targeted protein degradation and highlights the therapeutic potential of DBVR-PTC-02 as a promising candidate for the treatment of pancreatic cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118085"},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073014","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}

引用次数: 0

Fine-tuning phenoxy silyl scaffolds for the development of glutathione-responsive prodrugs and antibody–drug conjugates

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118088

Ding Wei , Huihui Wang , Shangwei Huangfu , Cheng Qi , Yuecheng Jiang , Xianqiang Yu , Biao Jiang , Hongli Chen

Silyl ether is particularly attractive for application in drug development for its easy preparation, non-toxicity and remarkable biocompatibility. Earlier studies relied on the use of intracellular acidic conditions to induce the cleavage of alkoxy silyl ethers. However, acidic conditions are not suitable to trigger the release of phenoxy silyl ethers, since they are more stable under acidic conditions compared with neutral conditions. We explored the vulnerability of the phenoxy silyl ether towards biological nucleophilic reagents and found that glutathione (GSH) could effectively and selectively induce the cleavage of phenoxy silyl ether. We also demonstrated that the rate of cleavage was controllable by adjusting the substituents on the phenyl ring. Phenoxy silyl ether-based prodrugs and antibody–drug conjugates (ADCs) were designed and synthesized, which could be effectively activated in cells with high GSH levels and there was an obvious therapeutic window between cells with different GSH levels.

{"title":"Fine-tuning phenoxy silyl scaffolds for the development of glutathione-responsive prodrugs and antibody–drug conjugates","authors":"Ding Wei , Huihui Wang , Shangwei Huangfu , Cheng Qi , Yuecheng Jiang , Xianqiang Yu , Biao Jiang , Hongli Chen","doi":"10.1016/j.bmc.2025.118088","DOIUrl":"10.1016/j.bmc.2025.118088","url":null,"abstract":"<div><div>Silyl ether is particularly attractive for application in drug development for its easy preparation, non-toxicity and remarkable biocompatibility. Earlier studies relied on the use of intracellular acidic conditions to induce the cleavage of alkoxy silyl ethers. However, acidic conditions are not suitable to trigger the release of phenoxy silyl ethers, since they are more stable under acidic conditions compared with neutral conditions. We explored the vulnerability of the phenoxy silyl ether towards biological nucleophilic reagents and found that glutathione (GSH) could effectively and selectively induce the cleavage of phenoxy silyl ether. We also demonstrated that the rate of cleavage was controllable by adjusting the substituents on the phenyl ring. Phenoxy silyl ether-based prodrugs and antibody–drug conjugates (ADCs) were designed and synthesized, which could be effectively activated in cells with high GSH levels and there was an obvious therapeutic window between cells with different GSH levels.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118088"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147543","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}

引用次数: 0

Janus dendritic ionizable lipids with fine designed headgroup and tails to improve mRNA delivery efficiency

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118080

Chao Liu, Yuhao Jiang, Wenliang Xue, Jinyu Liu, Zihao Wang, Xinsong Li

Lipid nanoparticles (LNP) are recognized as the most efficient non-viral carriers for the delivery of nucleic acids including small interfering RNA (siRNA) and messenger RNA (mRNA). Ionizable lipid within the system is pivotal component influencing encapsulation, endosomal escape, delivery efficiency and immunogenicity. Accordingly, the precision design of ionizable lipids is a key step in the development of LNP. In this report, we constructed sixteen Janus dendritic ionizable lipids by varying numbers and alkyl chain length of tails based on different ionizable head containing hydroxyl and tertiary amine groups. The corresponding LNP were prepared by using microfluidic mixing device, with all samples exhibiting particle size around 100 nm and polydispersity index (PDI) below 0.2. In vivo validation demonstrates that two optimized ionizable lipids containing two hydroxy groups, two tertiary amines and six hydrophobic chain tails (U-502, U-503) show superior delivery efficiency compared to lipids with less tails and commercial ALC-0315. Hematoxylin and Eosin (H&E) staining of tissues, immunogenicity, liver and kidney function tests additionally confirm that both ionizable lipids have favorable biocompatibility and low in vivo toxicity. Lysosomal escape and cell transfection data verify the in vitro delivery efficacy of these LNP. Taken together, Janus dendritic lipids with fine designed ionizable head and multiple hydrophobic tails have improved mRNA delivery efficiency and biosafety, which may be promise in the development of delivery system.

{"title":"Janus dendritic ionizable lipids with fine designed headgroup and tails to improve mRNA delivery efficiency","authors":"Chao Liu, Yuhao Jiang, Wenliang Xue, Jinyu Liu, Zihao Wang, Xinsong Li","doi":"10.1016/j.bmc.2025.118080","DOIUrl":"10.1016/j.bmc.2025.118080","url":null,"abstract":"<div><div>Lipid nanoparticles (LNP) are recognized as the most efficient non-viral carriers for the delivery of nucleic acids including small interfering RNA (siRNA) and messenger RNA (mRNA). Ionizable lipid within the system is pivotal component influencing encapsulation, endosomal escape, delivery efficiency and immunogenicity. Accordingly, the precision design of ionizable lipids is a key step in the development of LNP. In this report, we constructed sixteen Janus dendritic ionizable lipids by varying numbers and alkyl chain length of tails based on different ionizable head containing hydroxyl and tertiary amine groups. The corresponding LNP were prepared by using microfluidic mixing device, with all samples exhibiting particle size around 100 nm and polydispersity index (PDI) below 0.2. <em>In vivo</em> validation demonstrates that two optimized ionizable lipids containing two hydroxy groups, two tertiary amines and six hydrophobic chain tails (U-502, U-503) show superior delivery efficiency compared to lipids with less tails and commercial ALC-0315. Hematoxylin and Eosin (H&E) staining of tissues, immunogenicity, liver and kidney function tests additionally confirm that both ionizable lipids have favorable biocompatibility and low <em>in vivo</em> toxicity. Lysosomal escape and cell transfection data verify the <em>in vitro</em> delivery efficacy of these LNP. Taken together, Janus dendritic lipids with fine designed ionizable head and multiple hydrophobic tails have improved mRNA delivery efficiency and biosafety, which may be promise in the development of delivery system.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118080"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077867","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}

引用次数: 0

Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118086

Kazuya Kobayashi , Chinami Taniguchi , Misaki Tanaka , Rani Kimura , Kaho Komurasaki , Meguru Kuwano , Mayu Ikemoto , Natsuki Kawakami , Shinya Oishi , Yasunao Hattori , Kenichi Akaji

Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure–activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.

{"title":"Development of novel BACE1 inhibitors with a hydroxyproline-derived N-amidinopyrrolidine scaffold","authors":"Kazuya Kobayashi , Chinami Taniguchi , Misaki Tanaka , Rani Kimura , Kaho Komurasaki , Meguru Kuwano , Mayu Ikemoto , Natsuki Kawakami , Shinya Oishi , Yasunao Hattori , Kenichi Akaji","doi":"10.1016/j.bmc.2025.118086","DOIUrl":"10.1016/j.bmc.2025.118086","url":null,"abstract":"<div><div>Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived <em>N</em>-amidinopyrrolidine scaffold. The initially synthesized derivative <strong>7a</strong> showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure–activity relationship studies showed that introducing a substituent at the <em>meta</em> position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative <strong>12f</strong>. In contrast, substituents at the <em>para</em> position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2<em>S</em>,4<em>R</em>)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118086"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143287857","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}

引用次数: 0

Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118089

Hua Yang , Mingmei Guo , Sumeng Guan, Yuanyuan Chang, Xiaoya Wu, Yinuo Wang, Ling Zhu, Moran Sun

While apoptosis activation has traditionally been considered as an anti-cancer mechanism, current research points to ferroptosis stimulation as a potentially effective cancer therapy. Glutathione peroxidase 4 (GPX4), an essential antioxidant enzyme, serves as a negative regulator of ferroptosis, and its targeted inhibition or degradation can efficiently induce this process. In this study, a potent ferroptosis inducer III-4 that bearing a benzo[b]thiophene moiety was developed by employing a sequential structure optimization process based on RSL-3 to inhibit cancer cells proliferation. At the same time, this cytotoxic activity could be reversed by ferroptosis inducer Fer-1, suggesting that III-4 functions as a ferroptosis inducer. The structure–activity relationship (SAR) of these compounds was also explored. At the cellular level, compound III-4 could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe²⁺-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that III-4 arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound III-4 is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.

{"title":"Design, synthesis and biological evaluation of benzo[b]thiophene analogues as novel ferroptosis inhibitor that inhibit fibrosarcoma cell proliferation","authors":"Hua Yang , Mingmei Guo , Sumeng Guan, Yuanyuan Chang, Xiaoya Wu, Yinuo Wang, Ling Zhu, Moran Sun","doi":"10.1016/j.bmc.2025.118089","DOIUrl":"10.1016/j.bmc.2025.118089","url":null,"abstract":"<div><div>While apoptosis activation has traditionally been considered as an anti-cancer mechanism, current research points to ferroptosis stimulation as a potentially effective cancer therapy. Glutathione peroxidase 4 (GPX4), an essential antioxidant enzyme, serves as a negative regulator of ferroptosis, and its targeted inhibition or degradation can efficiently induce this process. In this study, a potent ferroptosis inducer <strong>III-4</strong> that bearing a benzo[<em>b</em>]thiophene moiety was developed by employing a sequential structure optimization process based on RSL-3 to inhibit cancer cells proliferation. At the same time, this cytotoxic activity could be reversed by ferroptosis inducer Fer-1, suggesting that <strong>III-4</strong> functions as a ferroptosis inducer. The structure–activity relationship (SAR) of these compounds was also explored. At the cellular level, compound <strong>III-4</strong> could block the generation of GSH, cause the accumulation of ROS and MDA, down-regulate GPX4 level, and finally trigger the Fe<sup>2+</sup>-mediated ferroptosis in HT1080 cell lines. Further biological investigation revealed that <strong>III-4</strong> arrested the cell cycle at the S phase and inhibited HT1080 cell lines migration. These results indicated that compound <strong>III-4</strong> is a candidate for the identification of novel ferroptosis inducer for fibrosarcoma cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118089"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147489","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}

引用次数: 0

Proteolysis targeting chimera of BI-2536 induces potent dual degradation of PLK1 and BET proteins

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-28 DOI: 10.1016/j.bmc.2025.118087

Shiwei Song, Wanrong Yang, Wanyi Tai

Polo-like kinase 1 (PLK1) and bromodomain 4 (BRD4) are well-known oncoproteins that drive tumor cell growth in many cancer types. Simultaneously targeting these protein targets has been intently pursued by scientists to enhance anti-cancer effect in chemotherapy. However, it is rare to design proteolytic targeting chimeras (PROTAC) to degrade these oncoproteins simultaneously by one single molecule. Herein, we designed and synthesized seven PROTAC molecules based on BI-2536, a dual-target inhibitor of BRD4 and PLK1. Among these, compound 17b demonstrated the best ability to degrade PLK1, BRD4 and other BET family proteins. The dual targeting PROTAC 17b induces the almost complete degradation of BET proteins and PLK1 at concentration as low as 3 nM, but proteolysis of PLK1 takes place a lot later than BET proteins (36 h vs 4 h). Compound 17b exhibited strong anti-proliferative activities across multiple cancer cell lines. Furthermore, 17b was able to regulate the expression of downstream genes involved in key cellular processes and exert the prolonged suppression of cancer cell growth. These findings suggest that 17b is a highly potent and efficacious dual-targeting degrader.

{"title":"Proteolysis targeting chimera of BI-2536 induces potent dual degradation of PLK1 and BET proteins","authors":"Shiwei Song, Wanrong Yang, Wanyi Tai","doi":"10.1016/j.bmc.2025.118087","DOIUrl":"10.1016/j.bmc.2025.118087","url":null,"abstract":"<div><div>Polo-like kinase 1 (PLK1) and bromodomain 4 (BRD4) are well-known oncoproteins that drive tumor cell growth in many cancer types. Simultaneously targeting these protein targets has been intently pursued by scientists to enhance anti-cancer effect in chemotherapy. However, it is rare to design proteolytic targeting chimeras (PROTAC) to degrade these oncoproteins simultaneously by one single molecule. Herein, we designed and synthesized seven PROTAC molecules based on BI-2536, a dual-target inhibitor of BRD4 and PLK1. Among these, compound 17b demonstrated the best ability to degrade PLK1, BRD4 and other BET family proteins. The dual targeting PROTAC 17b induces the almost complete degradation of BET proteins and PLK1 at concentration as low as 3 nM, but proteolysis of PLK1 takes place a lot later than BET proteins (36 h <em>vs</em> 4 h). Compound 17b exhibited strong anti-proliferative activities across multiple cancer cell lines. Furthermore, 17b was able to regulate the expression of downstream genes involved in key cellular processes and exert the prolonged suppression of cancer cell growth. These findings suggest that 17b is a highly potent and efficacious dual-targeting degrader.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118087"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143147962","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}

引用次数: 0

Discovery of novel spirocyclic derivates as potent androgen receptor antagonists

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-01-27 DOI: 10.1016/j.bmc.2025.118082

Wenqiang Zhang , Xiaoyu Zhou , Hao Zhu , Yawen Fan , Zhuolin Chen , Chenxiao Wang , Xingru Chen , Hongmei Li , Tao Lu , Xian Wei , Yadong Chen , Caiping Chen , Yu Jiao

We report herein the development of a series of novel AR antagonists characterized by a spirocyclic scaffold, employing scaffold hopping and structure-based drug design strategies. Most of the spirocyclic derivatives exhibited enhanced AR antagonistic activity and superior antiproliferative activity against LNCaP cells compared to enzalutamide. Among them, compound 21 demonstrated moderate antiproliferative activity against enzalutamide resistant prostate cancer cell lines and exhibited favorable in vitro metabolic stability. These findings offer valuable insights for the rational design of AR antagonists for the treatment of advanced prostate cancer.

引用次数: 0

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