Pub Date : 2024-10-22DOI: 10.1021/acs.jmedchem.4c01908
Gang Xu, Qiongyue Liang, Lijuan Gao, Shihang Xu, Weicong Luo, Qiuming Wu, Jingyuan Li, Zhenlei Zhang, Hong Liang, Feng Yang
To effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC), we developed a high-efficiency and low-toxicity arene ruthenium (Ru) complex based on apoferritin (AFt). To achieve this, we optimized a series of Ru(II) 1,10-phenanthroline-2,9-diformaldehyde thiosemicarbazone complexes by studying their structure−activity relationships to obtain an arene binuclear Ru(II) complex (C5) with significant cytotoxicity and high accumulation in the mitochondria of tumor cells. Subsequently, a C5-AFt nanoparticle (NPs) delivery system was constructed. We found that the C5/C5-AFt NPs effectively inhibited TNBC growth and metastasis with few side effects. The C5-AFt NPs improved the anticancer and targeting abilities of C5 in vivo. Moreover, we confirmed the mechanism by which C5/C5-AFt NPs inhibit tumor growth and metastasis via mitochondrial damage-mediated ferroptosis and activation of the cGAS-STING pathway.
{"title":"Developing an Arene Binuclear Ruthenium(II) Complex to Induce Ferroptosis and Activate the cGAS-STING Pathway: Targeted Inhibiting Growth and Metastasis of Triple Negative Breast Cancer","authors":"Gang Xu, Qiongyue Liang, Lijuan Gao, Shihang Xu, Weicong Luo, Qiuming Wu, Jingyuan Li, Zhenlei Zhang, Hong Liang, Feng Yang","doi":"10.1021/acs.jmedchem.4c01908","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01908","url":null,"abstract":"To effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC), we developed a high-efficiency and low-toxicity arene ruthenium (Ru) complex based on apoferritin (AFt). To achieve this, we optimized a series of Ru(II) 1,10-phenanthroline-2,9-diformaldehyde thiosemicarbazone complexes by studying their structure−activity relationships to obtain an arene binuclear Ru(II) complex (C5) with significant cytotoxicity and high accumulation in the mitochondria of tumor cells. Subsequently, a C5-AFt nanoparticle (NPs) delivery system was constructed. We found that the C5/C5-AFt NPs effectively inhibited TNBC growth and metastasis with few side effects. The C5-AFt NPs improved the anticancer and targeting abilities of C5 in vivo. Moreover, we confirmed the mechanism by which C5/C5-AFt NPs inhibit tumor growth and metastasis via mitochondrial damage-mediated ferroptosis and activation of the cGAS-STING pathway.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486492","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 : 2024-10-22DOI: 10.1021/acs.jmedchem.4c02083
Jennifer X. Qiao, David Williams, Patrice Gill, Ling Li, Derek Norris, John S. Tokarski, Jessica Wong, Huilin Qi, Yamnah Hafeji, Daniel P. Downes, Bill Degnen, Ying-Kai Wang, Gregory Locke, Hua Fang, Fei Yu, Songmei Xu, Joseph Naglich, Jun Zhang, Purushothama Nanjappa, Chao Dai, Lisa Chourb, Jonathan Napoline, Richland Tester, Christine Jorge, Yi-Xin Li, Arvind Mathur, Christopher Barbieri, Matthew G. Soars, Avinashnarayan Venkatanarayan, Emma Lees, Robert M. Borzilleri, Ashvinikumar V. Gavai, Michael Wichroski, T. G. Murali Dhar
We describe the design, synthesis, and structure–activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound 39. LDD 39 demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.
{"title":"Discovery and Synthesis of Heterobifunctional Degraders of Rearranged during Transfection (RET) Kinase","authors":"Jennifer X. Qiao, David Williams, Patrice Gill, Ling Li, Derek Norris, John S. Tokarski, Jessica Wong, Huilin Qi, Yamnah Hafeji, Daniel P. Downes, Bill Degnen, Ying-Kai Wang, Gregory Locke, Hua Fang, Fei Yu, Songmei Xu, Joseph Naglich, Jun Zhang, Purushothama Nanjappa, Chao Dai, Lisa Chourb, Jonathan Napoline, Richland Tester, Christine Jorge, Yi-Xin Li, Arvind Mathur, Christopher Barbieri, Matthew G. Soars, Avinashnarayan Venkatanarayan, Emma Lees, Robert M. Borzilleri, Ashvinikumar V. Gavai, Michael Wichroski, T. G. Murali Dhar","doi":"10.1021/acs.jmedchem.4c02083","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02083","url":null,"abstract":"We describe the design, synthesis, and structure–activity relationship (SAR) of heterobifunctional RET ligand-directed degraders (LDDs) derived from three different second-generation RET inhibitors. These LDDs are composed of a target binding motif (TBM) that binds to the RET protein, a linker, and a cereblon binding motif (CBM) as the E3 ligase recognition unit. This led to the identification of a series of pyrazolopyridine-based heterobifunctional LDDs, as exemplified by compound <b>39</b>. LDD <b>39</b> demonstrated high in vitro inhibitory and degradation potency against both RET wild-type and the two representative mutants, V804M and G810R. Importantly, in PK/PD studies, <b>39</b> exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound <b>3</b>. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD <b>39</b> at 15 and 75 mg/kg, respectively.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486423","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}
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.
{"title":"Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability","authors":"Zhuqian Wang, Siran Yue, Xinxin Chen, Jin Li, Peixi Zhu, Hongzhen Chen, Fang Qiu, Duoli Xie, Yiying Liang, Defang Li, Aiping Lu, Chao Liang","doi":"10.1021/acs.jmedchem.4c01228","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01228","url":null,"abstract":"Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487137","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 : 2024-10-21DOI: 10.1021/acs.jmedchem.4c01698
Yue Wu, Zewei Zhang, Haiping Cai, Weiqing Zhang, Linjian Zhang, Zhihong Li, Le Yang, Yafen Chen, Thomas P. Corner, Zhe Song, Jie Yue, Fulai Yang, Xiang Li, Christopher J. Schofield, Xiaojin Zhang
Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. ZG-2305, with a Ki of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of ZG-2305 in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate ZG-2305 has good pharmacokinetic properties and an acceptable safety profile. The results imply ZG-2305 is a promising candidate for treatment of obesity and fatty liver disease.
2-氧代戊二酸加氧酶抑制低氧诱导因子（FIH）的基因缺失会增强糖酵解和有氧代谢。因此，FIH 是控制脂肪和改善肝脏脂肪变性的潜在靶点。我们介绍了一系列新型、强效和选择性 FIH 抑制剂的开发情况，这些抑制剂同时占据 FIH 催化位点和最近定义的酪氨酸构象翻转口袋。ZG-2305 对 FIH 的 Ki 值为 79.6 nM，其选择性是缺氧诱导因子（HIF）脯氨酰羟化酶 PHD2 的 38 倍。在西式饮食诱导的肥胖小鼠模型中口服 ZG-2305 可改善脂质积累，恢复正常体重/肝脂肪变性。在高频-CDAA-饮食诱导的 NASH 小鼠模型中，观察到非酒精性脂肪性肝炎（NASH）相关病理表型得到改善。初步临床前研究表明，ZG-2305 具有良好的药代动力学特性和可接受的安全性。这些结果表明 ZG-2305 是治疗肥胖症和脂肪肝的理想候选药物。
{"title":"Discovery of ZG-2305, an Orally Bioavailable Factor Inhibiting HIF Inhibitor for the Treatment of Obesity and Fatty Liver Disease","authors":"Yue Wu, Zewei Zhang, Haiping Cai, Weiqing Zhang, Linjian Zhang, Zhihong Li, Le Yang, Yafen Chen, Thomas P. Corner, Zhe Song, Jie Yue, Fulai Yang, Xiang Li, Christopher J. Schofield, Xiaojin Zhang","doi":"10.1021/acs.jmedchem.4c01698","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01698","url":null,"abstract":"Genetic loss of the 2-oxoglutarate oxygenase factor inhibiting hypoxia-inducible factor (FIH) enhances both glycolysis and aerobic metabolism. FIH is thus a potential target for adiposity control and improving hepatic steatosis. We describe development of a series of novel, potent, and selective FIH inhibitors that occupy both the FIH catalytic site and a recently defined tyrosine conformational-flip pocket. <b>ZG-2305</b>, with a <i>K</i><sub>i</sub> of 79.6 nM for FIH, manifests 38-fold selectivity over the hypoxia-inducible factor (HIF) prolyl hydroxylase PHD2. Oral administration of <b>ZG-2305</b> in the western-diet induced obesity mouse model results in improved lipid accumulation and recovery from abnormal body weight/hepatic steatosis. Amelioration of nonalcoholic steatohepatitis (NASH) related pathological phenotypes in the HF-CDAA-diet induced NASH mouse model was observed. Preliminary preclinical studies indicate <b>ZG-2305</b> has good pharmacokinetic properties and an acceptable safety profile. The results imply <b>ZG-2305</b> is a promising candidate for treatment of obesity and fatty liver disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452329","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}
Developing drugs for treating glioblastoma has been a significant challenge. Herein, a series of arene ruthenium(II) complexes have been synthesized and investigated as potential candidates to suppress the proliferation and metastasis of glioblastoma. It is found that para-substituent-modified molecules, especially 6, exhibit higher antitumor activity than ortho-substituents. Further studies show that 6 can trigger tumor cell autophagy by regulating the PI3K/AKT/mTOR pathway. Moreover, it is also found that 6 can induce DNA damage in glioblastoma cells through binding and stabilizing VEGF G-quadruplex DNA. Furthermore, it is confirmed that 6 can inhibit the proliferation and metastasis of U87-MG glioblastoma cell in situ xenograft in the zebrafish model. Hence, arene ruthenium(II) complexes can be developed as promising therapeutic agents for glioblastoma treatment in the future.
开发治疗胶质母细胞瘤的药物一直是一项重大挑战。本文合成了一系列炔钌(II)配合物，并将其作为抑制胶质母细胞瘤增殖和转移的潜在候选化合物进行了研究。研究发现，对位取代基修饰的分子，尤其是 6，比正位取代基表现出更高的抗肿瘤活性。进一步的研究表明，6 能通过调节 PI3K/AKT/mTOR 通路引发肿瘤细胞自噬。此外，研究还发现，6 还能通过结合和稳定 VEGF G-quadruplex DNA 来诱导胶质母细胞瘤细胞的 DNA 损伤。此外，研究还证实 6 能抑制斑马鱼模型中 U87-MG 胶质母细胞瘤细胞原位异种移植的增殖和转移。因此，芴钌(II)配合物可被开发为未来治疗胶质母细胞瘤的药物。
{"title":"Discovery of Arene Ruthenium(II) Complexes as Potential VEGF Inhibitors for Glioblastoma Metastasis Suppression","authors":"Chanling Yuan, Chunguang Zhu, Qingshuang Lv, Jiahui Shi, Jiacheng Wang, Shiqi Gao, Jiayi Qian, Yanhua Chen, Qiong Wu, Wenjie Mei","doi":"10.1021/acs.jmedchem.4c00797","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00797","url":null,"abstract":"Developing drugs for treating glioblastoma has been a significant challenge. Herein, a series of arene ruthenium(II) complexes have been synthesized and investigated as potential candidates to suppress the proliferation and metastasis of glioblastoma. It is found that para-substituent-modified molecules, especially <b>6</b>, exhibit higher antitumor activity than ortho-substituents. Further studies show that <b>6</b> can trigger tumor cell autophagy by regulating the PI3K/AKT/mTOR pathway. Moreover, it is also found that <b>6</b> can induce DNA damage in glioblastoma cells through binding and stabilizing VEGF G-quadruplex DNA. Furthermore, it is confirmed that <b>6</b> can inhibit the proliferation and metastasis of U87-MG glioblastoma cell in situ xenograft in the zebrafish model. Hence, arene ruthenium(II) complexes can be developed as promising therapeutic agents for glioblastoma treatment in the future.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142452218","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 : 2024-10-21DOI: 10.1021/acs.jmedchem.4c01090
Yui Ishizaka, Hiroyuki Watanabe, Masahiro Ono
The orexin 1 receptor (OX1R) has been suggested to be involved in the reward and autonomic nervous systems. Positron emission tomography (PET) of OX1R contributes to elucidating its role and developing new drugs. However, there are no useful PET probes for in vivo imaging of OX1R. Here, we newly designed and synthesized 18F-labeled 1,4-diazepane derivatives and evaluated their utilities as OX1R PET probes. In particular, BTF showed high and selective binding affinity for OX1R. In a biodistribution study using normal mice, [18F]BTF exhibited brain uptake, and radioactivity in the brain was significantly decreased by preinjection of unlabeled BTF. In a PET/CT study, it was suggested that [18F]BTF has the potential to visualize high-expression regions of OX1R in the normal mouse brain. Collectively, [18F]BTF has the fundamental features of an OX1R PET probe, and further studies may lead to the development of more useful probes.
奥曲肽 1 受体（OX1R）被认为参与了奖赏和自律神经系统。OX1R 的正电子发射断层扫描（PET）有助于阐明其作用和开发新药。然而，目前还没有用于 OX1R 体内成像的 PET 探针。在此，我们新设计并合成了 18F 标记的 1,4-二氮杂环庚烷衍生物，并评估了它们作为 OX1R PET 探针的效用。其中，BTF 对 OX1R 具有很高的选择性结合亲和力。在一项使用正常小鼠进行的生物分布研究中，[18F]BTF 表现出脑摄取，而脑中的放射性在预先注射未标记的 BTF 后显著降低。PET/CT 研究表明，[18F]BTF 有可能显示正常小鼠大脑中 OX1R 的高表达区域。总之，[18F]BTF 具有 OX1R PET 探针的基本特征，进一步的研究可能会开发出更有用的探针。
{"title":"Structure-Affinity-Pharmacokinetics Relationships of Novel 18F-Labeled 1,4-Diazepane Derivatives for Orexin 1 Receptor Imaging","authors":"Yui Ishizaka, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acs.jmedchem.4c01090","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01090","url":null,"abstract":"The orexin 1 receptor (OX1R) has been suggested to be involved in the reward and autonomic nervous systems. Positron emission tomography (PET) of OX1R contributes to elucidating its role and developing new drugs. However, there are no useful PET probes for in vivo imaging of OX1R. Here, we newly designed and synthesized <sup>18</sup>F-labeled 1,4-diazepane derivatives and evaluated their utilities as OX1R PET probes. In particular, BTF showed high and selective binding affinity for OX1R. In a biodistribution study using normal mice, [<sup>18</sup>F]BTF exhibited brain uptake, and radioactivity in the brain was significantly decreased by preinjection of unlabeled BTF. In a PET/CT study, it was suggested that [<sup>18</sup>F]BTF has the potential to visualize high-expression regions of OX1R in the normal mouse brain. Collectively, [<sup>18</sup>F]BTF has the fundamental features of an OX1R PET probe, and further studies may lead to the development of more useful probes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451894","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}
Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-a]pyrimidone-based ABCB1 modulators. Notably, WS-917 was identified as a significant contributor to heightened sensitization of human colorectal adenocarcinoma cells (SW620/Ad300) to paclitaxel (IC50 = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [3H]-paclitaxel, concurrently mitigating the efflux of [3H]-paclitaxel in SW620/Ad300 through the inhibition of ABCB1 efflux. The cellular thermal shift assay underscored its ability to stabilize ABCB1 through direct binding. Additionally, WS-917 induced stimulation of ABCB1 ATPase activity while exhibiting negligible inhibitory effect against CYP3A4. Remarkable was its capacity to enhance the sensitivity of SW620/Ad300 to paclitaxel, as well as the sensitivity of CT26/TAXOL to paclitaxel and PD-L1 inhibitor (Atezolizumab) in vivo, all achieved without inducing observable toxicity. The discovery of WS-917 holds promise for the development of more potent ABCB1 modulators.
{"title":"Cell-Based Screen Identifies a Highly Potent and Orally Available ABCB1 Modulator for Treatment of Multidrug Resistance","authors":"Shuai Wang, Sai-Qi Wang, Xiao-Bing Chen, Qian Xu, Hao Deng, Qiu-Xu Teng, Zhe-Sheng Chen, Xuyao Zhang, Fen-Er Chen","doi":"10.1021/acs.jmedchem.4c01081","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01081","url":null,"abstract":"Targeting ABCB1 is a promising strategy in combating multidrug resistance. Our cell-based phenotypic screening led to the discovery of novel triazolo[1,5-<i>a</i>]pyrimidone-based ABCB1 modulators. Notably, <b>WS-917</b> was identified as a significant contributor to heightened sensitization of human colorectal adenocarcinoma cells (SW620/Ad300) to paclitaxel (IC<sub>50</sub> = 5 nM). Mechanistic elucidation revealed that this compound substantially augmented intracellular paclitaxel and [<sup>3</sup>H]-paclitaxel, concurrently mitigating the efflux of [<sup>3</sup>H]-paclitaxel in SW620/Ad300 through the inhibition of ABCB1 efflux. The cellular thermal shift assay underscored its ability to stabilize ABCB1 through direct binding. Additionally, <b>WS-917</b> induced stimulation of ABCB1 ATPase activity while exhibiting negligible inhibitory effect against CYP3A4. Remarkable was its capacity to enhance the sensitivity of SW620/Ad300 to paclitaxel, as well as the sensitivity of CT26/TAXOL to paclitaxel and PD-L1 inhibitor (Atezolizumab) in vivo, all achieved without inducing observable toxicity. The discovery of <b>WS-917</b> holds promise for the development of more potent ABCB1 modulators.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449732","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 : 2024-10-19DOI: 10.1021/acs.jmedchem.4c01320
Charline Giroud, Tamas Szommer, Carmen Coxon, Octovia Monteiro, Thomas Grimes, Tryfon Zarganes-Tzitzikas, Thomas Christott, James Bennett, Karly Buchan, Paul E. Brennan, Oleg Fedorov
The S100 protein family functions as protein–protein interaction adaptors regulated by Ca2+ binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein–protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. 5b showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action.
{"title":"Covalent Inhibitors of S100A4 Block the Formation of a Pro-Metastasis Non-Muscle Myosin 2A Complex","authors":"Charline Giroud, Tamas Szommer, Carmen Coxon, Octovia Monteiro, Thomas Grimes, Tryfon Zarganes-Tzitzikas, Thomas Christott, James Bennett, Karly Buchan, Paul E. Brennan, Oleg Fedorov","doi":"10.1021/acs.jmedchem.4c01320","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01320","url":null,"abstract":"The S100 protein family functions as protein–protein interaction adaptors regulated by Ca<sup>2+</sup> binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein–protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. <b>5b</b> showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450099","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 : 2024-10-19DOI: 10.1021/acs.jmedchem.4c02093
Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla
Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic Plasmodium parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic Plasmodium yoelii infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage Plasmodium berghei sporozoite-induced infection in mice.
{"title":"Optimization of B-Ring-Functionalized Antimalarial Tambjamines and Prodiginines","authors":"Amrendra Kumar, Sivanna Chithanna, Yuexin Li, Xiaowei Zhang, Rozalia A. Dodean, Diana Caridha, Michael S. Madejczyk, Patricia J. Lee, Xiannu Jin, Ravi Chetree, Cameron Blount, William E. Dennis, Jesse DeLuca, Chau Vuong, Kristina Pannone, Hieu T. Dinh, Susan Leed, Alison Roth, Kevin A. Reynolds, Jane X. Kelly, Papireddy Kancharla","doi":"10.1021/acs.jmedchem.4c02093","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02093","url":null,"abstract":"Malaria has been a deadly enemy of mankind throughout history, affecting over 200 million people annually, along with approximately half a million deaths. Resistance to current therapies is of great concern, and there is a dire need for novel and well-tolerated antimalarials that operate by clinically unexploited mechanisms. We have previously reported that both tambjamines and prodiginines are highly potent novel antiplasmodial agents, but they required rigor optimizations to enhance the oral efficacy, safety, and physicochemical properties. Here, we launched a comprehensive structure–activity relationship study for B-ring-functionalized tambjamines and prodiginines with 54 novel analogues systematically designed and synthesized. A number of compounds exhibited remarkable antiplasmodial activities against asexual erythrocytic <i>Plasmodium</i> parasites, with improved safety and metabolic profiles. Notably, several prodiginines cured erythrocytic <i>Plasmodium yoelii</i> infections after oral 25 mg/kg × 4 days in a murine model and provided partial protection against liver stage <i>Plasmodium berghei</i> sporozoite-induced infection in mice.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450010","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}
In our study to investigate the impact of two newly synthesized compounds (XP5 and XP19) alongside a positive control drug (CAY10603) on the expression levels of various target proteins─specifically, AC-α-Tubulin, α-Tubulin, SMC3, Ac-H3, H3, Ac-SMC3, and apoptosis-related antibodies (Ac-Ku70, Ku70, Bcl-2, Bax)─we conducted a series of experiments on different tumor cell lines, including Jurkat-T cells and B16-F10 cells. This comprehensive analysis yielded a substantial amount of experimental data and protein bands. Regrettably, during the assembly of Figure 7 and Figure 8 in the original manuscript, we inadvertently used a wrong image of Ac-Ku70 and Ku70 in Figure 7A and of Ac-SMC3, SMC3, and Ac-H3 in Figure 8E,F. Upon recent and careful review of the original manuscript, we identified this error and have replaced the wrong image with the correct one in the corrected Figure 7 and Figure 8. This corrected result still demonstrates that XP5 and XP19 can upregulate the expression levels of acetylated Ku70 significantly and dose-dependently but showed no effect on the Ku70 levels and had little effect on the levels of acetyl-SMC3 and acetyl-H3, and these corrections do not change the scientific conclusions of the article in any way. Figure 7. Analysis of acetylated Ku70, Ku70, Bcl-2, and Bax by Western blot. Jurkat T cells were treated with dimethyl sulfoxide (DMSO) or XP5, and XP19 for 6 h. The levels of acetylated Ku70, Ku70, Bcl-2, and Bax were examined by Western blot (A). Quantitative analysis of the levels of acetylated Ku70 (B), Bcl-2 (C), and Bax (D). All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01, *<i>p</i> < 0.05 compared with the control group, <sup>###</sup><i>p</i> < 0.001. One-way ANOVA for the above analysis, Dunnett test. Figure 8. Analysis of acetylated α-tubulin/acetylated-SMC3 and acetylated-H3 by Western blot. The levels of acetyl-α-tubulin (Ac-α-Tub) and α-tubulin in B16-F10 cells (A) and Jurkat T cells (B) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. Quantitative analysis of the level of acetyl-α-tubulin (Ac-α-Tub) by Western blotting assay obtained in B16-F10 cells (C) and Jurkat T cells (D). The levels of acetylated-SMC3, total SMC3, acetylated-H3, and total H3 in B16-F10 cells (E) and Jurkat T cells (F) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01 compared with the control group, <sup>###</sup><i>p</i> < 0.001, <sup>&</sup><i>p</i> < 0.05, <sup>&&</sup><i>p</i> < 0.01. One-way ANOVA for the above analysis, Dunnett test. We have now corrected the original Figure 7 and Figure 8, and all authors have agreed to the changes. We apologize for any confusion this may have caused and appreciate your understanding as we make these necessary corrections to ensure the integrity of our
{"title":"Correction to “Discovery of Novel Histone Deacetylase 6 (HDAC6) Inhibitors with Enhanced Antitumor Immunity of Anti-PD-L1 Immunotherapy in Melanoma”","authors":"Xiaopeng Peng, Ling Li, Jingxuan Chen, Yichang Ren, Jin Liu, Ziwen Yu, Hao Cao, Jianjun Chen","doi":"10.1021/acs.jmedchem.4c02486","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02486","url":null,"abstract":"In our study to investigate the impact of two newly synthesized compounds (XP5 and XP19) alongside a positive control drug (CAY10603) on the expression levels of various target proteins─specifically, AC-α-Tubulin, α-Tubulin, SMC3, Ac-H3, H3, Ac-SMC3, and apoptosis-related antibodies (Ac-Ku70, Ku70, Bcl-2, Bax)─we conducted a series of experiments on different tumor cell lines, including Jurkat-T cells and B16-F10 cells. This comprehensive analysis yielded a substantial amount of experimental data and protein bands. Regrettably, during the assembly of Figure 7 and Figure 8 in the original manuscript, we inadvertently used a wrong image of Ac-Ku70 and Ku70 in Figure 7A and of Ac-SMC3, SMC3, and Ac-H3 in Figure 8E,F. Upon recent and careful review of the original manuscript, we identified this error and have replaced the wrong image with the correct one in the corrected Figure 7 and Figure 8. This corrected result still demonstrates that XP5 and XP19 can upregulate the expression levels of acetylated Ku70 significantly and dose-dependently but showed no effect on the Ku70 levels and had little effect on the levels of acetyl-SMC3 and acetyl-H3, and these corrections do not change the scientific conclusions of the article in any way. Figure 7. Analysis of acetylated Ku70, Ku70, Bcl-2, and Bax by Western blot. Jurkat T cells were treated with dimethyl sulfoxide (DMSO) or XP5, and XP19 for 6 h. The levels of acetylated Ku70, Ku70, Bcl-2, and Bax were examined by Western blot (A). Quantitative analysis of the levels of acetylated Ku70 (B), Bcl-2 (C), and Bax (D). All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01, *<i>p</i> < 0.05 compared with the control group, <sup>###</sup><i>p</i> < 0.001. One-way ANOVA for the above analysis, Dunnett test. Figure 8. Analysis of acetylated α-tubulin/acetylated-SMC3 and acetylated-H3 by Western blot. The levels of acetyl-α-tubulin (Ac-α-Tub) and α-tubulin in B16-F10 cells (A) and Jurkat T cells (B) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. Quantitative analysis of the level of acetyl-α-tubulin (Ac-α-Tub) by Western blotting assay obtained in B16-F10 cells (C) and Jurkat T cells (D). The levels of acetylated-SMC3, total SMC3, acetylated-H3, and total H3 in B16-F10 cells (E) and Jurkat T cells (F) treated with DMSO or XP5, XP19, and CAY10603 for 6 h. All data are representative of three independent experiments and shown as mean ± SD. ***<i>p</i> < 0.001, **<i>p</i> < 0.01 compared with the control group, <sup>###</sup><i>p</i> < 0.001, <sup>&</sup><i>p</i> < 0.05, <sup>&&</sup><i>p</i> < 0.01. One-way ANOVA for the above analysis, Dunnett test. We have now corrected the original Figure 7 and Figure 8, and all authors have agreed to the changes. We apologize for any confusion this may have caused and appreciate your understanding as we make these necessary corrections to ensure the integrity of our","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450012","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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