Pub Date : 2024-12-17DOI: 10.1021/acs.jmedchem.4c02451
Dmitry A. Bunin, Roman A. Akasov, Alexander G. Martynov, Maria P. Stepanova, Svetlana V. Monich, Aslan Yu. Tsivadze, Yulia G. Gorbunova
To investigate the influence of phthalocyanine aggregation on their photodynamic activity, a series of six cationic water-soluble zinc(II) phthalocyanines bearing from four to sixteen 4-((diethylmethylammonium)methyl)phenoxy substituents was synthesized. Depending on their structure, the phthalocyanines have different aggregation behaviors in phosphate buffer solutions ranging from fully assembled to monomeric states. Remarkably, independent of aggregation in buffer, very high photodynamic efficiencies against the tumor cell lines MCF-7 and MDA-MB-231 in the nanomolar range were found for all investigated phthalocyanine, and the IC50(light) varied from 27 to 358 nM (3.5 J/cm2, 660 nm) with IC50(dark)/IC50(light) ratios up to ∼3700. This is due to the intracellular disassembly of aggregated phthalocyanines with the formation of monomeric photoactive forms, as demonstrated by fluorescence microscopy. Indeed, the interaction of aggregated phthalocyanines with serum proteins in a buffer resulted in the disassembly of nonluminescent aggregate species with the release of photoactive monomers bound to protein macromolecules.
{"title":"Pivotal Role of the Intracellular Microenvironment in the High Photodynamic Activity of Cationic Phthalocyanines","authors":"Dmitry A. Bunin, Roman A. Akasov, Alexander G. Martynov, Maria P. Stepanova, Svetlana V. Monich, Aslan Yu. Tsivadze, Yulia G. Gorbunova","doi":"10.1021/acs.jmedchem.4c02451","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02451","url":null,"abstract":"To investigate the influence of phthalocyanine aggregation on their photodynamic activity, a series of six cationic water-soluble zinc(II) phthalocyanines bearing from four to sixteen 4-((diethylmethylammonium)methyl)phenoxy substituents was synthesized. Depending on their structure, the phthalocyanines have different aggregation behaviors in phosphate buffer solutions ranging from fully assembled to monomeric states. Remarkably, independent of aggregation in buffer, very high photodynamic efficiencies against the tumor cell lines MCF-7 and MDA-MB-231 in the nanomolar range were found for all investigated phthalocyanine, and the IC<sub>50</sub>(light) varied from 27 to 358 nM (3.5 J/cm<sup>2</sup>, 660 nm) with IC<sub>50</sub>(dark)/IC<sub>50</sub>(light) ratios up to ∼3700. This is due to the intracellular disassembly of aggregated phthalocyanines with the formation of monomeric photoactive forms, as demonstrated by fluorescence microscopy. Indeed, the interaction of aggregated phthalocyanines with serum proteins in a buffer resulted in the disassembly of nonluminescent aggregate species with the release of photoactive monomers bound to protein macromolecules.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832882","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 : 2024-12-17DOI: 10.1021/acs.jmedchem.4c02047
Andrew McGrath, Haiyan Huang, Jean-Francois Brazeau, Zirong Zhang, Christopher O. Audu, Nadeem A. Vellore, Lu Zhu, Zhicai Shi, Jennifer D. Venable, Christine F. Gelin, Tim Cernak
Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine–acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.
{"title":"Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions","authors":"Andrew McGrath, Haiyan Huang, Jean-Francois Brazeau, Zirong Zhang, Christopher O. Audu, Nadeem A. Vellore, Lu Zhu, Zhicai Shi, Jennifer D. Venable, Christine F. Gelin, Tim Cernak","doi":"10.1021/acs.jmedchem.4c02047","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02047","url":null,"abstract":"Protein degradation using proteolysis targeting chimeras (PROTACs) represents a promising therapeutic strategy. PROTACs are heterobifunctional molecules that consist of a target-binding moiety and an E3 ligase binding moiety, connected by a linker. These fragments are frequently united via amide bonds. While straightforward to synthesize, amides may impart suboptimal drug properties to the overall molecule. From a systems level perspective, we envisioned that the potency of PROTACs could be modulated through selection of reaction conditions─wherein different catalysts produce distinct linkers from the same two building blocks. We present a suite of BRD4 PROTAC degraders prepared via four new amine–acid coupling reactions alongside the classic amide coupling. Our findings reveal that variations in reaction conditions affect the physicochemical properties of PROTACs, resulting in a spectrum of properties. Notably, several new PROTACs demonstrated enhanced BRD4 degradation efficacy compared to those employing amide linkers, emphasizing the potential of systems chemistry as a therapeutic optimization strategy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"122 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833043","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 search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel N-trifluoromethylated noscapines has been disclosed. Among them, 9′-bromo-N-trifluoromethyl noscapine 15c displayed superior in vitro anti-GBM potency. Unexpectedly, in contrast with the general N-trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where N-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, 15c showed excellent BBB permeability and good in vivo anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that 15c exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.
{"title":"Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma","authors":"Guangwei Cui, Yuhang Fan, Yue Yang, Yiwen Ma, Haiyang Deng, Pan Wang, Yuxin Zhu, Jian Li, Jinlian Wei, Yongqiang Zhang","doi":"10.1021/acs.jmedchem.4c01786","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01786","url":null,"abstract":"The search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel <i>N</i>-trifluoromethylated noscapines has been disclosed. Among them, 9′-bromo-<i>N</i>-trifluoromethyl noscapine <b>15c</b> displayed superior <i>in vitro</i> anti-GBM potency. Unexpectedly, in contrast with the general <i>N</i>-trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where <i>N</i>-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, <b>15c</b> showed excellent BBB permeability and good <i>in vivo</i> anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that <b>15c</b> exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832877","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.4c02344
Huu Bao Nguyen, Hyun Park, Jeong Eun Lim, Thuy Tien Nguyen, Hwan Hui Kim, Kyeongwon Kim, Jung Young Kim, Kyo Chul Lee, Jeongsoo Yoo
Radiolabeled antibodies are promising for targeted cancer imaging, but their structural integrity may suffer during bioconjugation and radiolabeling, leading to undetected aggregation. This study evaluates dynamic light scattering (DLS) as a complementary method to size-exclusion high-performance liquid chromatography (SEC-HPLC) for detecting aggregation in radiolabeled antibodies. Trastuzumab was conjugated with a NOTA bifunctional chelator at various ratios, radiolabeled with [64Cu]CuCl2, and analyzed by using DLS and SEC-HPLC before and after purification. DLS revealed significant aggregation during preparation, undetected by SEC-HPLC, and showed reduced aggregates following purification. Tumor-targeting efficacy correlated with intact antibody content, with Pearson’s correlations of 0.71 (PET imaging) and 0.75 (biodistribution) in NIH3T6.7 tumor-bearing mice. The findings suggest DLS as a vital quality control tool, offering enhanced detection of antibody aggregation. By adopting DLS, the bioactivity of radiolabeled antibodies can be better predicted, potentially improving the reliability and effectiveness of these radiopharmaceuticals in clinical settings.
{"title":"Evaluation of Dynamic Light Scattering as an Effective Quality Control Method for Aggregates in Radiolabeled Antibodies","authors":"Huu Bao Nguyen, Hyun Park, Jeong Eun Lim, Thuy Tien Nguyen, Hwan Hui Kim, Kyeongwon Kim, Jung Young Kim, Kyo Chul Lee, Jeongsoo Yoo","doi":"10.1021/acs.jmedchem.4c02344","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02344","url":null,"abstract":"Radiolabeled antibodies are promising for targeted cancer imaging, but their structural integrity may suffer during bioconjugation and radiolabeling, leading to undetected aggregation. This study evaluates dynamic light scattering (DLS) as a complementary method to size-exclusion high-performance liquid chromatography (SEC-HPLC) for detecting aggregation in radiolabeled antibodies. Trastuzumab was conjugated with a NOTA bifunctional chelator at various ratios, radiolabeled with [<sup>64</sup>Cu]CuCl<sub>2</sub>, and analyzed by using DLS and SEC-HPLC before and after purification. DLS revealed significant aggregation during preparation, undetected by SEC-HPLC, and showed reduced aggregates following purification. Tumor-targeting efficacy correlated with intact antibody content, with Pearson’s correlations of 0.71 (PET imaging) and 0.75 (biodistribution) in NIH3T6.7 tumor-bearing mice. The findings suggest DLS as a vital quality control tool, offering enhanced detection of antibody aggregation. By adopting DLS, the bioactivity of radiolabeled antibodies can be better predicted, potentially improving the reliability and effectiveness of these radiopharmaceuticals in clinical settings.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"122 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832881","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.4c01646
Malaika D. Argade, Jazmin Galván Achi, Ryan Bott, Kimberly M. Morsheimer, Callum D. Owen, Christian A. Zielinski, Arsen M. Gaisin, Mario Alvarez, Terry W. Moore, Fan Bu, Fang Li, Michael Cameron, Manu Anantpadma, Robert A. Davey, Norton P. Peet, Lijun Rong, Irina N. Gaisina
Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round of structure–activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound 1, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for in vivo efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.
埃博拉病毒和马尔堡病毒（EBOV 和 MARV）丝状病毒感染会导致致命的出血热，在过去 50 年中已造成 30 多起疫情爆发。目前，美国食品和药物管理局尚未批准有效治疗丝状病毒疾病的小分子疗法。为了满足这一尚未满足的医疗需求，我们对早期先导化合物 N-(4-(4-甲基哌啶-1-基)-3-(三氟甲基)苯基)-4-(吗啉甲基)苯甲酰胺 (1) 进行了系统的结构优化。结构-活性关系（SAR）的第二轮研究包括设计和合成化合物 1 的几种解构和重构类似物，然后针对假型 EBOV 和 MARV 进行测试。最有希望的先导化合物的抗病毒活性在感染性试验中得到了进一步验证。优化后的类似物对不同的伊波拉病毒具有理想的抗病毒活性，并减少了脱靶活性。此外，它们还具有类似药物的特性，使其成为体内药效研究的理想候选药物，这也是我们正在进行的抗 EBOV 和 MARV 药物研发活动的一部分。
{"title":"Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses","authors":"Malaika D. Argade, Jazmin Galván Achi, Ryan Bott, Kimberly M. Morsheimer, Callum D. Owen, Christian A. Zielinski, Arsen M. Gaisin, Mario Alvarez, Terry W. Moore, Fan Bu, Fang Li, Michael Cameron, Manu Anantpadma, Robert A. Davey, Norton P. Peet, Lijun Rong, Irina N. Gaisina","doi":"10.1021/acs.jmedchem.4c01646","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01646","url":null,"abstract":"Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, <i>N</i>-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (<b>1</b>), borne from our previously reported hit-to-lead effort. This secondary round of structure–activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound <b>1</b>, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for <i>in vivo</i> efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"251 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832888","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 emerged apoptosis/ferroptosis synergistic platinum-based therapy has attracted a lot of attention but is far from clinic use due to high systemic toxicity. Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (5NPs–8NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated by high-glutathione/ascorbic acid and acidity environment to produce an “explosion-like” cascade release process. Cell-activity showed precision of FSPNPs, which accumulated more in tumor cells and inhibited cell proliferation. Especially, 5NPs have higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde, induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to trigger the apoptosis/ferroptosis hybrid pathway. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.
新出现的铂类凋亡/铁突变协同疗法备受关注，但由于全身毒性较大，还远未应用于临床。本文通过将非诺贝特酸（FA）与顺铂或奥沙利铂衍生的铂(IV)中间体以二硫键连接，构建了一系列具有脂质调节作用的新型无载体精确自组装铂(IV)纳米颗粒，命名为FSPNPs（5NPs-8NPs）。FSPNPs 可在高谷胱甘肽/抗坏血酸和酸性环境的刺激下产生 "爆炸式 "级联释放过程。细胞活性显示，FSPNPs 在肿瘤细胞中积累较多，能抑制细胞增殖。尤其是 5NPs 比顺铂具有更高的细胞选择性。FSPNPs 下调谷胱甘肽/谷胱甘肽过氧化物酶 4，增加活性氧/脂质过氧化/丙二醛，诱导 DNA 损伤/S 期停滞，并调节 p53/Bcl-2/Bax，引发细胞凋亡/铁凋亡混合途径。释放出的 FA 及其衍生物与过氧化物酶体增殖激活受体α对接，激活胆固醇代谢，破坏膜的完整性。FSPNPs 还表现出良好的生物相容性和卓越的抗肿瘤活性，且无明显的组织损伤。
{"title":"Precise Carrier-Free Pt(IV)-Nanobombs for Apoptosis/Ferroptosis Synergistic Tumor Therapy: A New Effective Method to Obtain Good Chemotherapy and Low Toxicity","authors":"Xu Guo, Xue-Jiao Liang, Jia-Le Liu, Zhi-Hui Li, Zhihao You, Dandan Zhao, Yali Song, Longfei Li, Xue-Qing Song","doi":"10.1021/acs.jmedchem.4c02034","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02034","url":null,"abstract":"The emerged apoptosis/ferroptosis synergistic platinum-based therapy has attracted a lot of attention but is far from clinic use due to high systemic toxicity. Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (<b>5</b>NPs–<b>8</b>NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated by high-glutathione/ascorbic acid and acidity environment to produce an “explosion-like” cascade release process. Cell-activity showed precision of FSPNPs, which accumulated more in tumor cells and inhibited cell proliferation. Especially, <b>5</b>NPs have higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde, induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to trigger the apoptosis/ferroptosis hybrid pathway. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833051","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.4c02425
Agathe Boos, Julien Most, Héloïse Cahuzac, Louis Moreira da Silva, François Daubeuf, Stéphane Erb, Sarah Cianférani, Oscar Hernandez-Alba, Constantin Semenchenko, Igor Dovgan, Sergii Kolodych, Alexandre Detappe, Françoise Dantzer, Alain Wagner, Maria Zeniou, Guilhem Chaubet
Antibody-drug conjugates (ADCs) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADCs should theoretically spare healthy tissues and diminish side effects in patients, off-target toxicity is still observed, all the more serious, as the drugs are extremely potent. In the quest toward safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was N-alkylated with a cleavable linker and the resulting linker-payload conjugated to free cysteines of antibodies. We show that trastuzumab-vincristine conjugates display subnanomolar potency in vitro on HER2-positive cells, 2 orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.
{"title":"Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents","authors":"Agathe Boos, Julien Most, Héloïse Cahuzac, Louis Moreira da Silva, François Daubeuf, Stéphane Erb, Sarah Cianférani, Oscar Hernandez-Alba, Constantin Semenchenko, Igor Dovgan, Sergii Kolodych, Alexandre Detappe, Françoise Dantzer, Alain Wagner, Maria Zeniou, Guilhem Chaubet","doi":"10.1021/acs.jmedchem.4c02425","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02425","url":null,"abstract":"Antibody-drug conjugates (ADCs) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADCs should theoretically spare healthy tissues and diminish side effects in patients, off-target toxicity is still observed, all the more serious, as the drugs are extremely potent. In the quest toward safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was <i>N</i>-alkylated with a cleavable linker and the resulting linker-payload conjugated to free cysteines of antibodies. We show that trastuzumab-vincristine conjugates display subnanomolar potency in vitro on HER2-positive cells, 2 orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832883","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.4c02341
Hao Cui, Guodong Zhang, Liyuan Zhang, Shilong Sun, Kang Yang, Aixin Gen, Penfeng Wang, Hui Wang, Qing-Qing Zhou, Hongmei Li, Yadong Chen, Yuqin Yao, Tao Lu, Lei Zhang, Yong Zhu
Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as a promising strategy for treating ALI by inhibiting necrosis and inflammation. In this study, a series of pyrazole derivatives were designed to specifically target HDAC6, among which compound 6 demonstrated high antinecroptotic activity (IC50 = 0.5 nM) and excellent selective HDAC6 inhibition (IC50 = 4.95 nM, HDAC1/HDAC6 = 251). Surprisingly, compound 6 also exhibited excellent HDAC6 degradation activity (DC50 = 0.96 nM) through mechanistic studies. Additionally, it demonstrated strong inhibitory effects on inflammatory proteins TNF-α, IL-1β, and IL-6, indicating significant anti-inflammatory activity. Moreover, in a mouse model of acetaminophen (APAP)-induced acute liver injury, compound 6 exhibited significant therapeutic and protective efficacy at a dose of 40 mg/kg. These findings confirm that compound 6 is a promising lead structure for combating ALI-related diseases and warrants further investigation.
{"title":"Discovery of N-Phenyl-5-propyl-1H-pyrazole-3-carboxamide, with Selective Inhibition and Degradation of HDAC6 for the Treatment of Acute Liver Injury","authors":"Hao Cui, Guodong Zhang, Liyuan Zhang, Shilong Sun, Kang Yang, Aixin Gen, Penfeng Wang, Hui Wang, Qing-Qing Zhou, Hongmei Li, Yadong Chen, Yuqin Yao, Tao Lu, Lei Zhang, Yong Zhu","doi":"10.1021/acs.jmedchem.4c02341","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02341","url":null,"abstract":"Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as a promising strategy for treating ALI by inhibiting necrosis and inflammation. In this study, a series of pyrazole derivatives were designed to specifically target HDAC6, among which compound <b>6</b> demonstrated high antinecroptotic activity (IC<sub>50</sub> = 0.5 nM) and excellent selective HDAC6 inhibition (IC<sub>50</sub> = 4.95 nM, HDAC1/HDAC6 = 251). Surprisingly, compound <b>6</b> also exhibited excellent HDAC6 degradation activity (DC<sub>50</sub> = 0.96 nM) through mechanistic studies. Additionally, it demonstrated strong inhibitory effects on inflammatory proteins TNF-α, IL-1β, and IL-6, indicating significant anti-inflammatory activity. Moreover, in a mouse model of acetaminophen (APAP)-induced acute liver injury, compound <b>6</b> exhibited significant therapeutic and protective efficacy at a dose of 40 mg/kg. These findings confirm that compound <b>6</b> is a promising lead structure for combating ALI-related diseases and warrants further investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"57 1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832880","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.4c01875
Felix Niemeier, Lisa-Marie Servos, Zisis Papadopoulos, Nicolás Montesdeoca, Kaixin Ni, Sascha Heinrich, Johannes Karges
Cancer remains one of the deadliest diseases worldwide, with some tumors proving difficult to treat and increasingly resistant to current therapies. Capitalizing on this, there is a need for new therapeutic agents with novel mechanisms of action. Among promising candidates, Fe(III) complexes have gained significant attention as potential chemotherapeutic agents. However, research on these compounds has been limited to a small number, leading to inefficiencies in drug discovery. This study addresses these limitations by developing a combinatorial library of 495 new Fe(III) complexes synthesized from aminophenol, hydroxybenzaldehyde, and pyridine derivatives. The compounds were screened for cytotoxicity against human breast adenocarcinoma and noncancerous fibroblasts, identifying a novel class of Fe(III) complexes with modest cancer cell selectivity. The lead compound effectively eradicated breast cancer tumor spheroids at low micromolar concentrations, highlighting the potential of this approach for rapid drug discovery.
{"title":"Combinatorial Synthesis toward the Discovery of Highly Cytotoxic Fe(III) Complexes","authors":"Felix Niemeier, Lisa-Marie Servos, Zisis Papadopoulos, Nicolás Montesdeoca, Kaixin Ni, Sascha Heinrich, Johannes Karges","doi":"10.1021/acs.jmedchem.4c01875","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01875","url":null,"abstract":"Cancer remains one of the deadliest diseases worldwide, with some tumors proving difficult to treat and increasingly resistant to current therapies. Capitalizing on this, there is a need for new therapeutic agents with novel mechanisms of action. Among promising candidates, Fe(III) complexes have gained significant attention as potential chemotherapeutic agents. However, research on these compounds has been limited to a small number, leading to inefficiencies in drug discovery. This study addresses these limitations by developing a combinatorial library of 495 new Fe(III) complexes synthesized from aminophenol, hydroxybenzaldehyde, and pyridine derivatives. The compounds were screened for cytotoxicity against human breast adenocarcinoma and noncancerous fibroblasts, identifying a novel class of Fe(III) complexes with modest cancer cell selectivity. The lead compound effectively eradicated breast cancer tumor spheroids at low micromolar concentrations, highlighting the potential of this approach for rapid drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"36 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833046","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.4c01673
Guang Huang, Rhiannon Stevens, Devon G. Hucek, Trupta Purohit, Shuangjiang Li, Hongzhi Miao, Elise Trost, Geoff Hewett, Bradley Clegg, Se Ra Park, Krishani Rajanayake, Bo Wen, Duxin Sun, Tomasz Cierpicki, Jolanta Grembecka
The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of 66s (AS-254s), a highly potent and selective ASH1L inhibitor (IC50 = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, 66s effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring MLL1 translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.
{"title":"Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors","authors":"Guang Huang, Rhiannon Stevens, Devon G. Hucek, Trupta Purohit, Shuangjiang Li, Hongzhi Miao, Elise Trost, Geoff Hewett, Bradley Clegg, Se Ra Park, Krishani Rajanayake, Bo Wen, Duxin Sun, Tomasz Cierpicki, Jolanta Grembecka","doi":"10.1021/acs.jmedchem.4c01673","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01673","url":null,"abstract":"The absent, small, or homeotic-like 1 (ASH1L) protein is a histone lysine methyltransferase that plays a crucial role in various cancers, including leukemia. Despite representing an attractive therapeutic target, only one class of ASH1L inhibitors was identified to date. Herein, we report development of advanced ASH1L inhibitors targeting the catalytic SET domain, which were designed to access previously unexplored binding pocket on ASH1L. Extensive medicinal chemistry combined with structure-based design led to identification of <b>66s</b> (<b>AS-254s</b>), a highly potent and selective ASH1L inhibitor (IC<sub>50</sub> = 94 nM), representing substantially improved inhibitory activity over previously reported compounds targeting ASH1L. Furthermore, <b>66s</b> effectively blocked cell proliferation and induced apoptosis and differentiation in leukemia cells harboring <i>MLL1</i> translocations. Overall, this work provides a high-quality chemical probe targeting the catalytic SET domain of ASH1L with increased inhibitory activity and cellular efficacy to study biological functions of ASH1L and potentially to develop novel anticancer therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"92 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832879","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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