Pub Date : 2024-12-16DOI: 10.1021/acs.jmedchem.4c01850
Zhongren Xu, Yu Liu, Jiaqi Yang, Fuwei Li, Wukun Liu
Chemotherapy has long been used in the clinical management of hepatocellular carcinoma (HCC), driving the development of anticancer chemotherapy drugs. Platinum complexes have attracted significant attention and have led to the creation of a series of platinum-based drugs used in diverse cancer treatments, including HCC. However, the clinical use of platinum drugs faces critical challenges due to drug resistance and side effects. Consequently, ongoing efforts have been devoted to the continuous development of new metal complexes with antitumor properties, aiming to serve as effective alternatives for HCC treatment. In this Perspective, we summarize and highlight the progress and relevant mechanisms related to new metal complexes in the treatment of HCC over the past decade. The development of metal complexes has the potential to further expand the scope of chemotherapy applications for HCC.
{"title":"Recent Advances of Metal Complexes in the Treatment of Hepatocellular Carcinoma","authors":"Zhongren Xu, Yu Liu, Jiaqi Yang, Fuwei Li, Wukun Liu","doi":"10.1021/acs.jmedchem.4c01850","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01850","url":null,"abstract":"Chemotherapy has long been used in the clinical management of hepatocellular carcinoma (HCC), driving the development of anticancer chemotherapy drugs. Platinum complexes have attracted significant attention and have led to the creation of a series of platinum-based drugs used in diverse cancer treatments, including HCC. However, the clinical use of platinum drugs faces critical challenges due to drug resistance and side effects. Consequently, ongoing efforts have been devoted to the continuous development of new metal complexes with antitumor properties, aiming to serve as effective alternatives for HCC treatment. In this Perspective, we summarize and highlight the progress and relevant mechanisms related to new metal complexes in the treatment of HCC over the past decade. The development of metal complexes has the potential to further expand the scope of chemotherapy applications for HCC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832899","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 : 2024-12-16DOI: 10.1021/acs.jmedchem.4c02552
Pascal Sander, Martin P. Schwalm, Andreas Krämer, Lewis Elson, Alexander Rasch, Benedikt Masberg, Roland Selig, Adrian Sievers-Engler, Michael Lämmerhofer, Susanne Müller, Stefan Knapp, Wolfgang Albrecht, Stefan A. Laufer
The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of cancer. In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (10), which shows off-target activity toward MLK3. We were able to develop highly active compounds in the single digit nanomolar range for MLK3. Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound 37 with an outstanding IC50 value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.
{"title":"Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example","authors":"Pascal Sander, Martin P. Schwalm, Andreas Krämer, Lewis Elson, Alexander Rasch, Benedikt Masberg, Roland Selig, Adrian Sievers-Engler, Michael Lämmerhofer, Susanne Müller, Stefan Knapp, Wolfgang Albrecht, Stefan A. Laufer","doi":"10.1021/acs.jmedchem.4c02552","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02552","url":null,"abstract":"The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of cancer. In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (<b>10</b>), which shows off-target activity toward MLK3. We were able to develop highly active compounds in the single digit nanomolar range for MLK3. Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound <b>37</b> with an outstanding IC<sub>50</sub> value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"141 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832893","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 : 2024-12-13DOI: 10.1021/acs.jmedchem.4c02959
Antonella Ciancetta, Maria Laura Bolognesi
We are pleased to introduce a Collection on “Drug Discovery in Italy” on behalf of the <i>Journal of Medicinal Chemistry</i>. Italy has a long tradition of excellence in drug discovery, with several drugs brought to the market. (1) Today, this tradition continues and the pharmaceutical sector is still one of the main drivers of the country’s economy. However, the sector is predominantly active in the production of active pharmaceutical ingredients (APIs), with only a few companies and highly specialized Contract Research Organizations (CROs) engaged in R&D. The main dissemination efforts are therefore made by academic medicinal chemists, who try their best, despite a wavering support from the Italian Ministry of Universities and Research (MUR). The Medicinal Chemistry Division of the Italian Chemical Society (781 members in 2024) plays an active role in promoting collaboration between all the drug discovery stakeholders in Italy, and established a permanent roundtable in September 2023. (2) The current situation is mirrored in the 208 manuscripts with corresponding authors affiliated with an Italian institution that were accepted for publication between January 2020 and August 2024 in the <i>Journal of Medicinal Chemistry</i>. An analysis based on institution type revealed that the majority (85%) of the publications feature corresponding authors working in academia, followed by contributions (9%) submitted by researchers working in national research centers or public research institutes managed by private foundations (e.g., the Italian Institute of Technology), and a minority (6%) of scientists working in industry. Interestingly, the majority (60%) of the publications from industry were contributed by researchers from Chiesi Farmaceutici S.p.A., whereas the other contributions were authored by researchers at Dompé Farmaceutici S.p.A. and Molecular Horizon srl, or at a Swiss multinational company (Novartis AG) or a German CRO (Aptuit srl, an Evotec company) based in Italy. To note, both Chiesi and Dompé belong to the so-called “Fab13”, (3) companies characterized by family control and a mission to keep a large part of their research and production in Italy, as well as their headquarters. Pleasingly, the publications covered a wide geographical distribution from Northern to Southern Italy, with 15 out of 20 Italian regions represented in the published research (Figure 1). The published work was distributed as follows: 40% of the publications featured corresponding authors affiliated with institutions in Northern Italy, followed by 36% and 24% of publications with corresponding authors working at institutions in Central and Southern Italy, respectively. These statistics are roughly in line with the demographic distribution within the Italian territory, whereby 46% of the population lives in Northern regions. To counteract depopulation and ensure a more homogeneous distribution of the funding, the National Recovery and Resilience Plan in 2021 (4)
{"title":"Journal of Medicinal Chemistry Collection: Drug Discovery in Italy","authors":"Antonella Ciancetta, Maria Laura Bolognesi","doi":"10.1021/acs.jmedchem.4c02959","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02959","url":null,"abstract":"We are pleased to introduce a Collection on “Drug Discovery in Italy” on behalf of the <i>Journal of Medicinal Chemistry</i>. Italy has a long tradition of excellence in drug discovery, with several drugs brought to the market. (1) Today, this tradition continues and the pharmaceutical sector is still one of the main drivers of the country’s economy. However, the sector is predominantly active in the production of active pharmaceutical ingredients (APIs), with only a few companies and highly specialized Contract Research Organizations (CROs) engaged in R&D. The main dissemination efforts are therefore made by academic medicinal chemists, who try their best, despite a wavering support from the Italian Ministry of Universities and Research (MUR). The Medicinal Chemistry Division of the Italian Chemical Society (781 members in 2024) plays an active role in promoting collaboration between all the drug discovery stakeholders in Italy, and established a permanent roundtable in September 2023. (2) The current situation is mirrored in the 208 manuscripts with corresponding authors affiliated with an Italian institution that were accepted for publication between January 2020 and August 2024 in the <i>Journal of Medicinal Chemistry</i>. An analysis based on institution type revealed that the majority (85%) of the publications feature corresponding authors working in academia, followed by contributions (9%) submitted by researchers working in national research centers or public research institutes managed by private foundations (e.g., the Italian Institute of Technology), and a minority (6%) of scientists working in industry. Interestingly, the majority (60%) of the publications from industry were contributed by researchers from Chiesi Farmaceutici S.p.A., whereas the other contributions were authored by researchers at Dompé Farmaceutici S.p.A. and Molecular Horizon srl, or at a Swiss multinational company (Novartis AG) or a German CRO (Aptuit srl, an Evotec company) based in Italy. To note, both Chiesi and Dompé belong to the so-called “Fab13”, (3) companies characterized by family control and a mission to keep a large part of their research and production in Italy, as well as their headquarters. Pleasingly, the publications covered a wide geographical distribution from Northern to Southern Italy, with 15 out of 20 Italian regions represented in the published research (Figure 1). The published work was distributed as follows: 40% of the publications featured corresponding authors affiliated with institutions in Northern Italy, followed by 36% and 24% of publications with corresponding authors working at institutions in Central and Southern Italy, respectively. These statistics are roughly in line with the demographic distribution within the Italian territory, whereby 46% of the population lives in Northern regions. To counteract depopulation and ensure a more homogeneous distribution of the funding, the National Recovery and Resilience Plan in 2021 (4)","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"5 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816200","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 : 2024-12-13DOI: 10.1021/acs.jmedchem.4c02074
H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Eric Therrien, Morgan Lawrenz, Mitsunori Kato, Mats Svensson, Felicia Gray, Kristian Jensen, Markus K. Dahlgren, Robert D. Pelletier, Karen Dingley, Jeffrey A. Bell, Zhijian Liu, Yuansong Jiang, Hua Zhou, Robert J. Skene, Zhe Nie
Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program’s progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.
{"title":"In Silico Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury","authors":"H. Rachel Lagiakos, Yefen Zou, Hideyuki Igawa, Eric Therrien, Morgan Lawrenz, Mitsunori Kato, Mats Svensson, Felicia Gray, Kristian Jensen, Markus K. Dahlgren, Robert D. Pelletier, Karen Dingley, Jeffrey A. Bell, Zhijian Liu, Yuansong Jiang, Hua Zhou, Robert J. Skene, Zhe Nie","doi":"10.1021/acs.jmedchem.4c02074","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02074","url":null,"abstract":"Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (<b>59</b>). Throughout the program’s progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge <i>in silico</i> tools. KAI-11101 displayed an excellent <i>in vitro</i> safety profile and showed neuroprotective properties in an <i>ex vivo</i> axon fragmentation assay as well as dose-dependent activity in a mouse PD model.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"73 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816198","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 : 2024-12-13DOI: 10.1021/acs.jmedchem.4c02766
Julia Kinsolving, Lukas Grätz, Jan Hendrik Voss, Bente Löw, Emily Shorter, Baptiste Jude, Johanna T Lanner, Stefan Löber, Peter Gmeiner, Gunnar Schulte
The Frizzled family (FZD1–10) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD7 and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD7 for cancer treatment. Structure-based virtual screening has identified compound 28, which inhibited WNT/β-catenin signaling based on the luciferase-based reporter gene TOPFlash assay. However, upon pharmacological validation, compound 28 rather acts as a potent Firefly luciferase (Fluc) inhibitor (IC50 = 30 nM), matching the reported IC50 for compound 28-mediated inhibition in the TOPFlash assay. Moreover, we employed Fluc-independent assays, a FZD7-focused bioluminescence resonance energy transfer biosensor and quantitative PCR, to emphasize the inability of compound 28 to inhibit the WNT-3A-induced conformational dynamics in FZD7 and transcription of Axin2, a WNT target gene. Thus, we underline the importance of counter screens to validate compounds that interfere with the detection technology used for compound screening.
{"title":"A Putative Frizzled 7-Targeting Compound Acts as a Firefly Luciferase Inhibitor","authors":"Julia Kinsolving, Lukas Grätz, Jan Hendrik Voss, Bente Löw, Emily Shorter, Baptiste Jude, Johanna T Lanner, Stefan Löber, Peter Gmeiner, Gunnar Schulte","doi":"10.1021/acs.jmedchem.4c02766","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02766","url":null,"abstract":"The Frizzled family (FZD<sub>1–10</sub>) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD<sub>7</sub> and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD<sub>7</sub> for cancer treatment. Structure-based virtual screening has identified compound 28, which inhibited WNT/β-catenin signaling based on the luciferase-based reporter gene TOPFlash assay. However, upon pharmacological validation, compound 28 rather acts as a potent Firefly luciferase (Fluc) inhibitor (IC<sub>50</sub> = 30 nM), matching the reported IC<sub>50</sub> for compound 28-mediated inhibition in the TOPFlash assay. Moreover, we employed Fluc-independent assays, a FZD<sub>7</sub>-focused bioluminescence resonance energy transfer biosensor and quantitative PCR, to emphasize the inability of compound 28 to inhibit the WNT-3A-induced conformational dynamics in FZD<sub>7</sub> and transcription of <i>Axin2,</i> a WNT target gene. Thus, we underline the importance of counter screens to validate compounds that interfere with the detection technology used for compound screening.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816199","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 : 2024-12-12Epub Date: 2024-11-28DOI: 10.1021/acs.jmedchem.4c02832
Luke M Shepherd
{"title":"Surviving Your First Week in Medicinal Chemistry.","authors":"Luke M Shepherd","doi":"10.1021/acs.jmedchem.4c02832","DOIUrl":"10.1021/acs.jmedchem.4c02832","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"20737-20739"},"PeriodicalIF":6.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737782","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c02554
Carson W. Reed, Jacob F. Kalbfleisch, Jeremy A. Turkett, Trevor A. Trombley, Anthony F. Nastase, Paul K. Spearing, Daniel H. Haymer, Mohammad Moshin Sarwar, Marc Quitalig, Jonathan W. Dickerson, Annie L. Blobaum, Olivier Boutaud, Patrizia Voehringer, Niklas Schuelert, Hyekyung P. Cho, Colleen M. Niswender, Jerri M. Rook, Henning Priepke, Daniel Ursu, P. Jeffrey Conn, Bruce J. Melancon, Craig W. Lindsley
Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu1) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC50 > 10 μM, 71% Glumax), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu2–5,7,8) and CNS penetrant (rat Kp = 0.99, Kp,uu = 0.82; MDCK-MDR1 ER = 1.7, Papp = 73 × 10–6 cm/s) mGlu1 PAM (VU6024578/BI02982816, EC50 = 54 nM, 83% Glumax). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu1 activation.
{"title":"Discovery of VU6024578/BI02982816: An MGlu1 Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models","authors":"Carson W. Reed, Jacob F. Kalbfleisch, Jeremy A. Turkett, Trevor A. Trombley, Anthony F. Nastase, Paul K. Spearing, Daniel H. Haymer, Mohammad Moshin Sarwar, Marc Quitalig, Jonathan W. Dickerson, Annie L. Blobaum, Olivier Boutaud, Patrizia Voehringer, Niklas Schuelert, Hyekyung P. Cho, Colleen M. Niswender, Jerri M. Rook, Henning Priepke, Daniel Ursu, P. Jeffrey Conn, Bruce J. Melancon, Craig W. Lindsley","doi":"10.1021/acs.jmedchem.4c02554","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02554","url":null,"abstract":"Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu<sub>1</sub>) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC<sub>50</sub> > 10 μM, 71% Glu<sub>max</sub>), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu<sub>2–5,7,8</sub>) and CNS penetrant (rat K<sub>p</sub> = 0.99, K<sub>p,uu</sub> = 0.82; MDCK-MDR1 ER = 1.7, P<sub>app</sub> = 73 × 10–6 cm/s) mGlu<sub>1</sub> PAM (VU6024578/BI02982816, EC<sub>50</sub> = 54 nM, 83% Glu<sub>max</sub>). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class <i>in vivo</i> rodent tool to study selective mGlu<sub>1</sub> activation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810027","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}
Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure–activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.
环表肽类化合物太阳神酰胺在抑制癌细胞增殖方面具有巨大潜力。我们之前的研究确定了太阳神酰胺的全合成和抗癌特性。然而，深入了解太阳神酰胺的结构-活性关系（SAR）仍是当务之急。在这项研究中，我们旨在阐明太阳神酰胺在体外和体内的 SAR 和作用机理。SAR 研究证实了双环和二硫化物在太阳神酰胺抗癌活性中的关键作用。我们最近的研究发现，太阳神酰胺靶向 TrxR1，导致产生 ROS 和 ER 应激介导的细胞凋亡，同时还通过靶向 Gpx4 促进脂质过氧化，使癌细胞易受铁变态反应的影响。在体内，实验证明了太阳神酰胺通过诱导细胞凋亡和铁凋亡来降低肿瘤生长的有效性。太阳神酰胺在诱导细胞凋亡和铁蛋白沉降方面的双重功效使其成为乳腺癌治疗的一个有希望的候选药物，从而应对化疗耐药性的挑战。
{"title":"Deciphering the Comprehensive Structure–Activity Relationship of Sunshinamide for Breast Cancer Therapy through Dual Modulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4 Inhibition","authors":"Akash Chatterjee, Joyanta Mondal, Subhojit Paul, Himangshu Sharma, Rajib Kumar Goswami, Prosenjit Sen","doi":"10.1021/acs.jmedchem.4c01902","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01902","url":null,"abstract":"Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure–activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816204","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c01747
Kristoffer Peterson, Ulf J. Nilsson, Lise Gravelle, Ian Holyer, Karl Jansson, Barbro Kahl-Knutson, Hakon Leffler, Alison C. MacKinnon, James A. Roper, Robert J. Slack, Henrik von Wachenfeldt, Anders Pedersen, Fredrik R. Zetterberg
The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, GB1211 (h-galectin-3 Kd = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including GB1211 (m-galectin-3 Kd = 0.77 μM). Pharmacokinetic experiments in mouse dosing GB1211 up to 100 mg/kg results in free plasma levels below m-galectin-3 Kd, which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound, GB2095, was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers.
{"title":"Development and Characterization of a High-Affinity Selective Galectin-3 Mouse Tool Compound in Mouse Models of Cancer","authors":"Kristoffer Peterson, Ulf J. Nilsson, Lise Gravelle, Ian Holyer, Karl Jansson, Barbro Kahl-Knutson, Hakon Leffler, Alison C. MacKinnon, James A. Roper, Robert J. Slack, Henrik von Wachenfeldt, Anders Pedersen, Fredrik R. Zetterberg","doi":"10.1021/acs.jmedchem.4c01747","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01747","url":null,"abstract":"The interest in galectin-3 as a drug target in the cancer and fibrosis space has grown during the past few years with several new classes of compounds being developed. The first orally available galectin-3 inhibitor, <b>GB1211</b> (h-galectin-3 K<sub>d</sub> = 0.025 μM), is currently in phase 2 clinical trials. Due to structural differences between human and mouse galectin-3 a significant reduction in mouse galectin-3 affinity is observed for most highly potent human galectin-3 inhibitors including <b>GB1211</b> (m-galectin-3 K<sub>d</sub> = 0.77 μM). Pharmacokinetic experiments in mouse dosing <b>GB1211</b> up to 100 mg/kg results in free plasma levels below m-galectin-3 K<sub>d</sub>, which is not comparable to the data observed in humans. To better support translation into clinical studies, a new improved mouse galectin-3 tool compound, <b>GB2095</b>, was developed. Dosing this new compound in in vivo syngeneic mouse models of cancer resulted in reduction of the growth of breast and melanoma cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"62 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816203","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 : 2024-12-12Epub Date: 2024-11-25DOI: 10.1021/acs.jmedchem.4c02178
Huirong Li, Yuelin Li, Ke Li, Qianhui Wang, Jichen Yang, Ling Qiu, Jianguo Lin
Cathepsin B (CTB) is overexpressed in several types of tumors, and precise evaluation of the CTB activity can offer a promising method for the early diagnosis of tumors. In this study, two CTB-activated positron emission tomography (PET) tracers, [68Ga]NOTA-SFCVM and [68Ga]NOTA-SFCVHEM, were developed for sensitive and specific detection of CTB. Both tracers undergo a click condensation between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) to form a cyclization product, thereby enhancing and prolonging the PET signal in tumors. In vitro cellular experiments showed that the tracers could differentiate tumor cells with different expression levels of CTB. In vivo PET imaging further revealed that the tracers selectively accumulated in the CTB-positive tumors. Compared with [68Ga]NOTA-SFCVM, [68Ga]NOTA-SFCVHEM containing a morpholine group and a histidine-glutamate-histidine-glutamate-histidine-glutamate sequence exhibited faster catalytic efficiency toward CTB, higher tumor uptake, and reduced liver uptake. These findings suggest that [68Ga]NOTA-SFCVHEM holds potential for clinical use in the early diagnosis of CTB-related tumors.
{"title":"Positron Emission Tomography Imaging of Cathepsin B in Tumors with Activable Small Molecule Tracers.","authors":"Huirong Li, Yuelin Li, Ke Li, Qianhui Wang, Jichen Yang, Ling Qiu, Jianguo Lin","doi":"10.1021/acs.jmedchem.4c02178","DOIUrl":"10.1021/acs.jmedchem.4c02178","url":null,"abstract":"<p><p>Cathepsin B (CTB) is overexpressed in several types of tumors, and precise evaluation of the CTB activity can offer a promising method for the early diagnosis of tumors. In this study, two CTB-activated positron emission tomography (PET) tracers, <b>[</b><sup><b>68</b></sup><b>Ga]NOTA-SFCVM</b> and <b>[</b><sup><b>68</b></sup><b>Ga]NOTA-SFCVHEM</b>, were developed for sensitive and specific detection of CTB. Both tracers undergo a click condensation between 2-cyano-6-aminobenzothiazole (CBT) and cysteine (Cys) to form a cyclization product, thereby enhancing and prolonging the PET signal in tumors. <i>In vitro</i> cellular experiments showed that the tracers could differentiate tumor cells with different expression levels of CTB. <i>In vivo</i> PET imaging further revealed that the tracers selectively accumulated in the CTB-positive tumors. Compared with <b>[</b><sup><b>68</b></sup><b>Ga]NOTA-SFCVM</b>, <b>[</b><sup><b>68</b></sup><b>Ga]NOTA-SFCVHEM</b> containing a morpholine group and a histidine-glutamate-histidine-glutamate-histidine-glutamate sequence exhibited faster catalytic efficiency toward CTB, higher tumor uptake, and reduced liver uptake. These findings suggest that <b>[</b><sup><b>68</b></sup><b>Ga]NOTA-SFCVHEM</b> holds potential for clinical use in the early diagnosis of CTB-related tumors.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"21292-21302"},"PeriodicalIF":6.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142714776","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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