Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c02361
Bjarne Due Larsen, Jesper Skodborg Villadsen, Jolanta Skarbaliene, Claes Melander, Wayne Russell, Yvette Miata Petersen, Eva Horn Møller
Human glucagon-like peptide-2 (hGLP-2) receptor agonists have a benefit for the treatment of short bowel syndrome (SBS) and potentially other intestinal diseases (e.g., IBD). Native hGLP-2, a 33-amino acid gastrointestinal hormone, has a short half-life and is chemically and physically unstable, rendering it unsuitable for clinical use. In this paper, we describe the design of novel hGLP-2 peptide analogues with significantly improved chemical and physical properties, high in vitro hGLP-2 receptor potencies, and extended half-lives. Furthermore, synthesis yields were significantly improved by the addition of a C-terminal (lysine)6 tail (Structure Inducing Probe technology, SIP). One hGLP-2 analogue described herein is glepaglutide ([Gly2Glu3Thr5Ser8Leu10Ala11,16,24,28] hGLP-2[1–33]-NH-[Lys]6-NH2), the first long-acting analogue with excellent physicochemical stability, making it suitable for liquid formulation. Glepaglutide is currently in phase 3 clinical trials as a potential new therapy for SBS and is the only hGLP-2 analogue in clinical testing that is dosed subcutaneously from a ready-to-use formulation in an autoinjector.
{"title":"Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection","authors":"Bjarne Due Larsen, Jesper Skodborg Villadsen, Jolanta Skarbaliene, Claes Melander, Wayne Russell, Yvette Miata Petersen, Eva Horn Møller","doi":"10.1021/acs.jmedchem.4c02361","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02361","url":null,"abstract":"Human glucagon-like peptide-2 (hGLP-2) receptor agonists have a benefit for the treatment of short bowel syndrome (SBS) and potentially other intestinal diseases (e.g., IBD). Native hGLP-2, a 33-amino acid gastrointestinal hormone, has a short half-life and is chemically and physically unstable, rendering it unsuitable for clinical use. In this paper, we describe the design of novel hGLP-2 peptide analogues with significantly improved chemical and physical properties, high <i>in vitro</i> hGLP-2 receptor potencies, and extended half-lives. Furthermore, synthesis yields were significantly improved by the addition of a C-terminal (lysine)<sub>6</sub> tail (Structure Inducing Probe technology, SIP). One hGLP-2 analogue described herein is glepaglutide ([Gly<sup>2</sup>Glu<sup>3</sup>Thr<sup>5</sup>Ser<sup>8</sup>Leu<sup>10</sup>Ala<sup>11,16,24,28</sup>] hGLP-2[1–33]-NH-[Lys]6-NH<sub>2</sub>), the first long-acting analogue with excellent physicochemical stability, making it suitable for liquid formulation. Glepaglutide is currently in phase 3 clinical trials as a potential new therapy for SBS and is the only hGLP-2 analogue in clinical testing that is dosed subcutaneously from a ready-to-use formulation in an autoinjector.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular glue degraders induce “undruggable” protein degradation by a proximity-induced effect. Inspired by the clinical success of immunomodulatory drugs, we aimed to design novel molecular glue degraders targeting GSPT1. Here, we report the design of a series of GSPT1 molecular glue degraders. LYG-409, a 2H-chromene derivative, was identified as a potent, selective, and orally bioavailable GSPT1 degrader with excellent antitumor activity in vivo (anti-Acute Myeloid Leukemia MV4–11 xenograft model: TGI = 94.34% at 30 mg/kg; prostate cancer 22Rv1 xenograft model: TGI = 104.49% at 60 mg/kg) and in vitro (KG-1 cells: IC50 = 9.50 ± 0.71 nM, DC50 = 7.87 nM) mediated by the degradation of GSPT1. In conclusion, LYG-409 exhibits potent GSPT1 degradation activity, demonstrating promising therapeutic efficacy and favorable safety profile. However, its potential drug resistance profile needs to be thoroughly evaluated in comparison with existing treatments. We hope LYG-409 can provide a valuable direction for the development of GSPT1 degraders.
{"title":"Design and Discovery of Preclinical Candidate LYG-409 as a Highly Potent and Selective GSPT1 Molecular Glue Degraders","authors":"Yanqing Zhang, Wenjing Liu, Chao Tong, Xinhong Wang, Xiujin Chang, Fangui Qu, Zhiming Zhang, Zhongpen Fan, Monong Zhao, Cheng Tang, Beichen Song, Ming Ding, Zhixia Qiu, Jubo Wang, Jinlei Bian, Zhiyu Li, Hongxi Wu, Xi Xu","doi":"10.1021/acs.jmedchem.4c01787","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01787","url":null,"abstract":"Molecular glue degraders induce “undruggable” protein degradation by a proximity-induced effect. Inspired by the clinical success of immunomodulatory drugs, we aimed to design novel molecular glue degraders targeting GSPT1. Here, we report the design of a series of GSPT1 molecular glue degraders. <b>LYG-409</b>, a 2<i>H</i>-chromene derivative, was identified as a potent, selective, and orally bioavailable GSPT1 degrader with excellent antitumor activity <i>in vivo</i> (anti-Acute Myeloid Leukemia MV4–11 xenograft model: TGI = 94.34% at 30 mg/kg; prostate cancer 22Rv1 xenograft model: TGI = 104.49% at 60 mg/kg) and <i>in vitro</i> (KG-1 cells: IC<sub>50</sub> = 9.50 ± 0.71 nM, DC<sub>50</sub> = 7.87 nM) mediated by the degradation of GSPT1. In conclusion, <b>LYG-409</b> exhibits potent GSPT1 degradation activity, demonstrating promising therapeutic efficacy and favorable safety profile. However, its potential drug resistance profile needs to be thoroughly evaluated in comparison with existing treatments. We hope <b>LYG-409</b> can provide a valuable direction for the development of GSPT1 degraders.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"52 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c02655
Hyunhwa La, Jinwoong Kim, Dae-Hoon Kim, Seong-Heon Kim, Pargat Singh, Gibeom Nam, Kyeongwon Moon, Ikyon Kim, In Su Kim
GPR119 has emerged as a promising target for treating type 2 diabetes and associated obesity, as its stimulation induces the secretion of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in the intestinal tract as well as the glucose-dependent release of insulin in pancreatic β-cells. We describe the design and synthesis of novel GPR119 agonists containing a 1,4-disubstituted cyclohexene scaffold. Compound 21b displayed nanomolar potency (EC50 = 3.8 nM) for hGPR119 activation and demonstrated a hypoglycemic efficacy of 17.0% in an oral glucose tolerance test. The hypoglycemic effect of compound 21b, compared to sitagliptin, a DPP-4 inhibitor, showed the relatively higher efficacy in both FATZO and db/db mice. Additionally, compound 21b exhibited a significant reduction in body weight in a female diet-induced obese rat model, comparable to that of metformin. Furthermore, in vivo pharmacokinetic experiments revealed that compound 21b is a potential candidate for the treatment of type 2 diabetes and obesity.
{"title":"Discovery of 1,4-Disubstituted Cyclohexene Analogues as Selective GPR119 Agonists for the Treatment of Type 2 Diabetes","authors":"Hyunhwa La, Jinwoong Kim, Dae-Hoon Kim, Seong-Heon Kim, Pargat Singh, Gibeom Nam, Kyeongwon Moon, Ikyon Kim, In Su Kim","doi":"10.1021/acs.jmedchem.4c02655","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02655","url":null,"abstract":"GPR119 has emerged as a promising target for treating type 2 diabetes and associated obesity, as its stimulation induces the secretion of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide in the intestinal tract as well as the glucose-dependent release of insulin in pancreatic β-cells. We describe the design and synthesis of novel GPR119 agonists containing a 1,4-disubstituted cyclohexene scaffold. Compound <b>21b</b> displayed nanomolar potency (EC<sub>50</sub> = 3.8 nM) for <i>h</i>GPR119 activation and demonstrated a hypoglycemic efficacy of 17.0% in an oral glucose tolerance test. The hypoglycemic effect of compound <b>21b</b>, compared to sitagliptin, a DPP-4 inhibitor, showed the relatively higher efficacy in both FATZO and db/db mice. Additionally, compound <b>21b</b> exhibited a significant reduction in body weight in a female diet-induced obese rat model, comparable to that of metformin. Furthermore, in vivo pharmacokinetic experiments revealed that compound <b>21b</b> is a potential candidate for the treatment of type 2 diabetes and obesity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC50) = 112 ± 8 nM] and BRD4-BD1 (IC50 = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.
{"title":"Design, Synthesis, and Biological Evaluation of Thieno[3,2-d]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors","authors":"Kai Ran, Jiu-Hong Huang, Yong Li, Yimei Zhang, Hao Hu, Zhengyu Wang, Dian-Yong Tang, Hong-yu Li, Zhi-Gang Xu, Zhong-Zhu Chen","doi":"10.1021/acs.jmedchem.4c02478","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02478","url":null,"abstract":"The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-<i>d</i>]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (<b>10b</b>) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC<sub>50</sub>) = 112 ± 8 nM] and BRD4-BD1 (IC<sub>50</sub> = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, <b>10b</b> has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c02702
Youzhi Li, Michel Nguyen, Marion Laurent, Sharon Wein, Lucie Paloque, Shivani Kessavdjee-Djouma, Benoît Witkowski, Lise Musset, Jean-Michel Augereau, Rachel Cerdan, Anne Robert, Yan Liu, Bernard Meunier, Françoise Benoit-Vical
To challenge the multidrug resistance of Plasmodium falciparum malaria parasites, new hybrid compounds were synthesized and evaluated against laboratory strains and multidrug-resistant clinical isolates. Among these hybrids, emoquine-1 was the most active on proliferative P. falciparum, with IC50 values in the range of 20–55 nM and a high selectivity index with respect to mammalian cells. This drug retained its activity on several multiresistant field isolates from Cambodia and Guiana, exhibited no cross-resistance to artemisinin, and is also very active against the quiescent stage of the artemisinin-resistant parasites, three features that constitute the gold standard for new antimalarial drugs. In vivo, emoquine-1 is active against Plasmodium vinckei petteri at 25 mg/kg/d per os and by the intraperitoneal route at 1–5 mg/kg/d, with total cure at 10 mg/kg/d, making emoquine-1 an ideal candidate to fight Plasmodium parasites resistant to artemisinin-based combination therapies (ACTs) with a capacity to eliminate persistent parasites.
{"title":"Emoquine-1: A Hybrid Molecule Efficient against Multidrug-Resistant Plasmodium Parasites, Including the Artemisinin-Resistant Quiescent Stage, and Also Active In Vivo","authors":"Youzhi Li, Michel Nguyen, Marion Laurent, Sharon Wein, Lucie Paloque, Shivani Kessavdjee-Djouma, Benoît Witkowski, Lise Musset, Jean-Michel Augereau, Rachel Cerdan, Anne Robert, Yan Liu, Bernard Meunier, Françoise Benoit-Vical","doi":"10.1021/acs.jmedchem.4c02702","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02702","url":null,"abstract":"To challenge the multidrug resistance of <i>Plasmodium falciparum</i> malaria parasites, new hybrid compounds were synthesized and evaluated against laboratory strains and multidrug-resistant clinical isolates. Among these hybrids, emoquine-1 was the most active on proliferative <i>P. falciparum</i>, with IC<sub>50</sub> values in the range of 20–55 nM and a high selectivity index with respect to mammalian cells. This drug retained its activity on several multiresistant field isolates from Cambodia and Guiana, exhibited no cross-resistance to artemisinin, and is also very active against the quiescent stage of the artemisinin-resistant parasites, three features that constitute the gold standard for new antimalarial drugs. <i>In vivo</i>, emoquine-1 is active against <i>Plasmodium vinckei</i> petteri at 25 mg/kg/d per os and by the intraperitoneal route at 1–5 mg/kg/d, with total cure at 10 mg/kg/d, making emoquine-1 an ideal candidate to fight <i>Plasmodium</i> parasites resistant to artemisinin-based combination therapies (ACTs) with a capacity to eliminate persistent parasites.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c03022
Jingyu Yang, Yan Wu, Yue-Yang Liu, Shang-Bo Yu, Ke Feng, Hui Wang, Wei Zhou, Da Ma, Gang Zhao, Jiaheng Zhang, Dan-Wei Zhang, Zhan-Ting Li
The combination of ultralong-acting neuromuscular block and subsequent on-demand rapid reversal may provide prolonged surgeries with improved conditions by omitting continuous or repetitive blocker administration, enabling a more stable and predictable hemodynamic profile and eliminating residual block. For this target, we prepared 19 imidazolium-incorporated tetracationic macrocycles. In vivo studies with rats revealed that one macrocycle (IMC-14) displays extremely high blocking activity. At the dose of 12.5-fold ED90, IMC-14 exhibits an onset time shorter than that of cisatracurium of 2-fold dose and a duration time corresponding to more than 13 h for human adults. Moreover, within the dose range of 12.5–187.5-fold ED90, the profound block induced by IMC-14 can be rapidly reversed at any stage by a highly biocompatible acyclic cucurbit[n]uril antagonist, with a reversal time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, a clinically widely used intermediate-acting neuromuscular blocking agent.
{"title":"Discovery of an Ultralong-acting Nondepolarizing Neuromuscular Blocker That Displays Short Onset Time and On-Demand Rapid Reversal by a Biocompatible Antagonist","authors":"Jingyu Yang, Yan Wu, Yue-Yang Liu, Shang-Bo Yu, Ke Feng, Hui Wang, Wei Zhou, Da Ma, Gang Zhao, Jiaheng Zhang, Dan-Wei Zhang, Zhan-Ting Li","doi":"10.1021/acs.jmedchem.4c03022","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03022","url":null,"abstract":"The combination of ultralong-acting neuromuscular block and subsequent on-demand rapid reversal may provide prolonged surgeries with improved conditions by omitting continuous or repetitive blocker administration, enabling a more stable and predictable hemodynamic profile and eliminating residual block. For this target, we prepared 19 imidazolium-incorporated tetracationic macrocycles. In vivo studies with rats revealed that one macrocycle (IMC-14) displays extremely high blocking activity. At the dose of 12.5-fold ED<sub>90</sub>, IMC-14 exhibits an onset time shorter than that of cisatracurium of 2-fold dose and a duration time corresponding to more than 13 h for human adults. Moreover, within the dose range of 12.5–187.5-fold ED<sub>90</sub>, the profound block induced by IMC-14 can be rapidly reversed at any stage by a highly biocompatible acyclic cucurbit[<i>n</i>]uril antagonist, with a reversal time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, a clinically widely used intermediate-acting neuromuscular blocking agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c02720
Shixuan Jiao, Qiang Ren, Lianru Chen, Zongtao Zhou, Zongyu Cai, Wanqiu Huang, Bin Wang, Siliang Chen, Wenxin Wang, Zhijun Cao, Zhongcheng Yang, Qiqing Ye, Luyong Zhang, Zheng Li
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist 2 as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator 6, with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound 6 exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator 6 is worthy of further evaluation as a novel anti-MASH agent.
{"title":"Discovery of First-in-Class FXR and HSD17B13 Dual Modulator for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease","authors":"Shixuan Jiao, Qiang Ren, Lianru Chen, Zongtao Zhou, Zongyu Cai, Wanqiu Huang, Bin Wang, Siliang Chen, Wenxin Wang, Zhijun Cao, Zhongcheng Yang, Qiqing Ye, Luyong Zhang, Zheng Li","doi":"10.1021/acs.jmedchem.4c02720","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02720","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist <b>2</b> as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator <b>6</b>, with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound <b>6</b> exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator <b>6</b> is worthy of further evaluation as a novel anti-MASH agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blocking mitosis is a promising strategy to induce tumor cell death. However, AMPK- and PFKFB3-mediated glycolysis can maintain ATP supply and help tumor cells overcome antimitotic drugs. Inhibiting glycolysis provides an opportunity to decrease the resistance of tumor cells to antimitotic drugs. Meanwhile, increased glutathione (GSH) expression in cancer cells due to glycolysis becomes a target for developing microenvironment-responsive drugs. Herein, a novel cationic lipid with disulfide bonds in hydrophobic tails was synthesized and used to prepare a GSH-triggered lipid nanoparticle named 2-DG@SLNP(siR) encapsulating both Plk1 siRNA and 2-deoxyglucose (2-DG) for blocking mitosis and reducing drug resistance of nonsmall cell lung cancer (NSCLC) cells in vivo. Experimental results showed that the NSCLC cell cycle was arrested at the G2/M phase by Plk1 siRNA and glycolysis was effectively inhibited by 2-DG, demonstrating the potential of 2-DG@SLNP(siR) as an efficient platform for blocking mitosis and reducing drug resistance of cancer cells.
{"title":"Tumor Microenvironment-Responsive Lipid Nanoparticle for Blocking Mitosis and Reducing Drug Resistance in NSCLC","authors":"Fengrui Yang, Xiao-Rou Jiang, Lingling Lei, Jing-Hao Fu, Zeng-Ping Chen, Ru-Qin Yu","doi":"10.1021/acs.jmedchem.4c02960","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02960","url":null,"abstract":"Blocking mitosis is a promising strategy to induce tumor cell death. However, AMPK- and PFKFB3-mediated glycolysis can maintain ATP supply and help tumor cells overcome antimitotic drugs. Inhibiting glycolysis provides an opportunity to decrease the resistance of tumor cells to antimitotic drugs. Meanwhile, increased glutathione (GSH) expression in cancer cells due to glycolysis becomes a target for developing microenvironment-responsive drugs. Herein, a novel cationic lipid with disulfide bonds in hydrophobic tails was synthesized and used to prepare a GSH-triggered lipid nanoparticle named 2-DG@SLNP(siR) encapsulating both Plk1 siRNA and 2-deoxyglucose (2-DG) for blocking mitosis and reducing drug resistance of nonsmall cell lung cancer (NSCLC) cells in vivo. Experimental results showed that the NSCLC cell cycle was arrested at the G2/M phase by Plk1 siRNA and glycolysis was effectively inhibited by 2-DG, demonstrating the potential of 2-DG@SLNP(siR) as an efficient platform for blocking mitosis and reducing drug resistance of cancer cells.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.5c00076
Congbao Kang, Weijun Xu
The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin–proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues. Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. By leveraging these tools, the next generation of molecular glues are expected to offer unprecedented opportunities for combating a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative conditions.
{"title":"Leveraging Structural and Computational Biology for Molecular Glue Discovery","authors":"Congbao Kang, Weijun Xu","doi":"10.1021/acs.jmedchem.5c00076","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00076","url":null,"abstract":"The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin–proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues. Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. By leveraging these tools, the next generation of molecular glues are expected to offer unprecedented opportunities for combating a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative conditions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"109 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.4c01691
Margot Boujut, Margaux Héritier, Aurélie Gouiller, Camille Süess, Alessandro Scapozza, Thibaut De Smedt, Maxime Guibert, Sébastien Tardy, Hesham M. Ismail, David Pejoski, Leonardo Scapozza
Inhibition of the adenosine 2A receptor (A2AR) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A2AR function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A2AR NAM scaffolds were identified, followed by an extensive structure–activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. The allosteric mode of action of active compounds was confirmed by progressive fold-shift assay, nonlinearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A2AR engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A2AR allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.
{"title":"Discovery of the First Efficacious Adenosine 2A Receptor Negative Allosteric Modulators for High Adenosine Cancer Immunotherapies","authors":"Margot Boujut, Margaux Héritier, Aurélie Gouiller, Camille Süess, Alessandro Scapozza, Thibaut De Smedt, Maxime Guibert, Sébastien Tardy, Hesham M. Ismail, David Pejoski, Leonardo Scapozza","doi":"10.1021/acs.jmedchem.4c01691","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01691","url":null,"abstract":"Inhibition of the adenosine 2A receptor (A<sub>2A</sub>R) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A<sub>2A</sub>R function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A<sub>2A</sub>R NAM scaffolds were identified, followed by an extensive structure–activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. The allosteric mode of action of active compounds was confirmed by progressive fold-shift assay, nonlinearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A<sub>2A</sub>R engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A<sub>2A</sub>R allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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