Matheus Andrade Meirelles, Vitor M. Almeida, Jaryd R. Sullivan, Ian de Toledo, Caio Vinicius dos Reis, Micael Rodrigues Cunha, Rachel Zigweid, Abraham Shim, Banumathi Sankaran, Elijah L. Woodward, Steve Seibold, Lijun Liu, Mohammad Rasel Mian, Kevin P. Battaile, Jennifer Riley, Christina Duncan, Frederick R. C. Simeons, Liam Ferguson, Halimatu Joji, Kevin D. Read, Scott Lovell, Bart L. Staker, Marcel A. Behr, Ronaldo A. Pilli, Rafael M. Couñago
{"title":"Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens","authors":"Matheus Andrade Meirelles, Vitor M. Almeida, Jaryd R. Sullivan, Ian de Toledo, Caio Vinicius dos Reis, Micael Rodrigues Cunha, Rachel Zigweid, Abraham Shim, Banumathi Sankaran, Elijah L. Woodward, Steve Seibold, Lijun Liu, Mohammad Rasel Mian, Kevin P. Battaile, Jennifer Riley, Christina Duncan, Frederick R. C. Simeons, Liam Ferguson, Halimatu Joji, Kevin D. Read, Scott Lovell, Bart L. Staker, Marcel A. Behr, Ronaldo A. Pilli, Rafael M. Couñago","doi":"10.1021/acs.jmedchem.4c01594","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01594","url":null,"abstract":"Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on <b>P218</b>, a malarial DHFR inhibitor. We identified compound <b>8</b>, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: <i>Mycobacterium avium</i> and <i>Mycobacterium abscessus</i>. This study underscores the potential of compound <b>8</b> as a promising candidate for the <i>in vivo</i> validation of DHFR as an effective treatment against NTM infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520154","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}
Grant Koch, Alexander Engstrom, Jaru Taechalertpaisarn, Justin Faris, Satoshi Ono, Matthew R. Naylor, R. Scott Lokey
{"title":"Chromatographic Determination of Permeability-Relevant Lipophilicity Facilitates Rapid Analysis of Macrocyclic Peptide Scaffolds","authors":"Grant Koch, Alexander Engstrom, Jaru Taechalertpaisarn, Justin Faris, Satoshi Ono, Matthew R. Naylor, R. Scott Lokey","doi":"10.1021/acs.jmedchem.4c01956","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01956","url":null,"abstract":"Hydrocarbon-determined shake-flask measurements have demonstrated great utility for optimizing lipophilicity during early drug discovery. Alternatively, chromatographic methods confer reduced experimental error and improved handling of complex mixtures. In this study, we developed a chromatographic approach for estimating hydrocarbon–water shake-flask partition coefficients for a variety of macrocyclic peptides and other bRo5 molecules including PROTACs. The model accurately predicts experimental shake-flask measurements with high reproducibility across a wide range of lipophilicities. The chromatographic retention times revealed subtle conformational effects and correlated with the ability to sequester hydrogen bond donors in low dielectric media. Estimations of shake-flask lipophilicity from our model also accurately predicted trends in MDCK passive cell permeability for a variety of thioether-cyclized decapeptides. This method provides a convenient, high-throughput approach for measuring lipophilic permeability efficiency and predicting passive cell permeability in bRo5 compounds that is suitable for multiplexing pure compounds or investigating the properties of complex library mixtures.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490042","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}
Antonius ter Laak, Roman C. Hillig, Steven J. Ferrara, Daniel Korr, Naomi Barak, Philip Lienau, Simon Herbert, Amaury Ernesto Fernández-Montalván, Roland Neuhaus, Mátyás Gorjánácz, Vera Puetter, Volker Badock, Wilhelm Bone, Craig Strathdee, Franziska Siegel, Christoph Schatz, Katrin Nowak-Reppel, Olaf Doehr, Stefan Gradl, Ingo V. Hartung, Matthew Meyerson, Léa Bouché
{"title":"Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor","authors":"Antonius ter Laak, Roman C. Hillig, Steven J. Ferrara, Daniel Korr, Naomi Barak, Philip Lienau, Simon Herbert, Amaury Ernesto Fernández-Montalván, Roland Neuhaus, Mátyás Gorjánácz, Vera Puetter, Volker Badock, Wilhelm Bone, Craig Strathdee, Franziska Siegel, Christoph Schatz, Katrin Nowak-Reppel, Olaf Doehr, Stefan Gradl, Ingo V. Hartung, Matthew Meyerson, Léa Bouché","doi":"10.1021/acs.jmedchem.4c01709","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01709","url":null,"abstract":"KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12–15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 (<b>29</b>), was successfully validated in an <i>in vivo</i> proof-of-concept study.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490028","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}
Xu Wang, Dimitar Gotchev, Kristi Yi Fan, Marvin M. Vega, Nagraj Mani, Kayleigh McGovern-Gooch, Andrea Cuconati, Breanna Tercero, Xiaohe Wang, Philip Carpino, Klaus Maskos, Paolo A. Centrella, Andreas Schmitt, Franziska Preuss, Archna Prasad, Chia-yi Chen, Matthew A. Clark, John P. Guilinger, Shawn Johnstone, Konstanze von König, Anthony D. Keefe, Jenny Liu, Stéphane Turcotte, Ying Zhang, Debora L. Konz Makino, Angela M. Lam, Andrew G. Cole, Michael J. Sofia
{"title":"Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 Mpro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants","authors":"Xu Wang, Dimitar Gotchev, Kristi Yi Fan, Marvin M. Vega, Nagraj Mani, Kayleigh McGovern-Gooch, Andrea Cuconati, Breanna Tercero, Xiaohe Wang, Philip Carpino, Klaus Maskos, Paolo A. Centrella, Andreas Schmitt, Franziska Preuss, Archna Prasad, Chia-yi Chen, Matthew A. Clark, John P. Guilinger, Shawn Johnstone, Konstanze von König, Anthony D. Keefe, Jenny Liu, Stéphane Turcotte, Ying Zhang, Debora L. Konz Makino, Angela M. Lam, Andrew G. Cole, Michael J. Sofia","doi":"10.1021/acs.jmedchem.4c02009","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02009","url":null,"abstract":"The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M<sup>pro</sup>) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M<sup>pro</sup> inhibitor was the first such approved therapy. Although M<sup>pro</sup> inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M<sup>pro</sup> inhibitor <b>5</b>, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone <b>12</b> with significantly improved antiviral activity. Further optimization led to the potent lactam <b>26</b>, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490029","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}
Beatrice Marinacci, Ilaria D’Agostino, Andrea Angeli, Simone Carradori, Francesco Melfi, Rossella Grande, Micol Corsiani, Marta Ferraroni, Mariangela Agamennone, Anna Rita Tondo, Susi Zara, Valentina Puca, Benedetta Pellegrini, Chiara Vagaggini, Elena Dreassi, Marianna A. Patrauchan, Clemente Capasso, Orazio Nicolotti, Fabrizio Carta, Claudiu T. Supuran
{"title":"Inhibition of Pseudomonas aeruginosa Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study","authors":"Beatrice Marinacci, Ilaria D’Agostino, Andrea Angeli, Simone Carradori, Francesco Melfi, Rossella Grande, Micol Corsiani, Marta Ferraroni, Mariangela Agamennone, Anna Rita Tondo, Susi Zara, Valentina Puca, Benedetta Pellegrini, Chiara Vagaggini, Elena Dreassi, Marianna A. Patrauchan, Clemente Capasso, Orazio Nicolotti, Fabrizio Carta, Claudiu T. Supuran","doi":"10.1021/acs.jmedchem.4c01555","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01555","url":null,"abstract":"Ciprofloxacin (CPX) is one of the most employed antibiotics in clinics to date. However, the rise of drug-resistant bacteria is dramatically impairing its efficacy, especially against life-threatening pathogens, such as <i>Pseudomonas aeruginosa</i>. This Gram-negative bacterium is an opportunistic pathogen, often infecting immuno-compromised patients with severe or fatal outcomes. The evidence of the possibility of exploiting Carbonic Anhydrase (CA, EC: 4.2.1.1) enzymes as pharmacological targets along with their role in <i>P. aeruginosa</i> virulence inspired the derivatization of CPX with peculiar CA-inhibiting chemotypes. Thus, a large library of CPX derivatives was synthesized and tested on a panel of bacterial CAs and human isoenzymes I and II. Selected derivatives were evaluated for antibacterial activity, revealing bactericidal and antibiofilm properties for some compounds. Importantly, promising preliminary absorption, distribution, metabolism, and excretion (ADME) properties <i>in vitro</i> were found and no cytotoxicity was detected for some representative compounds when tested in <i>Galleria mellonella</i> larvae.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490040","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}
Haobing Wang, Dan Li, Hanqiang Wang, Qingyan Ren, Yue Pan, Anyi Dao, Deliang Wang, Zhigang Wang, Pingyu Zhang, Huaiyi Huang
{"title":"Enhanced Sonodynamic Therapy for Deep Tumors Using a Self-Assembled Organoplatinum(II) Sonosensitizer.","authors":"Haobing Wang, Dan Li, Hanqiang Wang, Qingyan Ren, Yue Pan, Anyi Dao, Deliang Wang, Zhigang Wang, Pingyu Zhang, Huaiyi Huang","doi":"10.1021/acs.jmedchem.4c01671","DOIUrl":"10.1021/acs.jmedchem.4c01671","url":null,"abstract":"<p><p>Despite the promising advances in photodynamic therapy (PDT), it remains challenging to target and treat deep-seated solid tumors effectively. Herein, we developed an organoplatinum(II) complex (<b>Pt-TPE</b>) with self-assembly properties for sonodynamic therapy (SDT). <b>Pt-TPE</b> forms a nanofiber network structure through Pt-Pt and π-π stacking interactions. Notably, under ultrasound (US), <b>Pt-TPE</b> demonstrates unique self-assembly-induced singlet oxygen (<sup>1</sup>O<sub>2</sub>) generation due to a significantly enhanced singlet-triplet intersystem crossing (ISC). This generation of <sup>1</sup>O<sub>2</sub> occurs exclusively in the self-assembled state of <b>Pt-TPE</b>. Additionally, <b>Pt-TPE</b> exhibits sono-cytotoxicity against cancer cells by impairing mitochondrial membrane potential (MMP), inhibiting glucose uptake, and aerobic glycolysis. Furthermore, US-activated <b>Pt-TPE</b> significantly inhibits deep solid tumors in mice, achieving remarkable therapeutic efficacy even at penetration depths greater than 10 cm. This study highlights the potential of self-assembled metal complexes to enhance the efficacy of SDT for treating deep tumors.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363446","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}
Yu Xu, Dan Liu, Wenzhuang Zhang, Zhining Liu, Jingjing Liu, Wanling Zhang, Rongxing Song, Jia Li, Fan Yang, Yue Wang, Dunkai Liu, Gaofei Qian, Hua Tang, Xijing Chen, Yisheng Lai
{"title":"Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.","authors":"Yu Xu, Dan Liu, Wenzhuang Zhang, Zhining Liu, Jingjing Liu, Wanling Zhang, Rongxing Song, Jia Li, Fan Yang, Yue Wang, Dunkai Liu, Gaofei Qian, Hua Tang, Xijing Chen, Yisheng Lai","doi":"10.1021/acs.jmedchem.4c01793","DOIUrl":"10.1021/acs.jmedchem.4c01793","url":null,"abstract":"<p><p>Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound <b>35j</b> proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (<i>T</i><sub>1/2</sub> = 3.37 h, <i>F</i> = 50.24%). Importantly, orally administered <b>35j</b> significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that <b>35j</b> remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that <b>35j</b> is a potent CD73 inhibitor worthy of further development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386400","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}
{"title":"Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy","authors":"Zhimin Zhang, Liubin Guo, Mengting Zhao, Hao Pan, Zhao Dong, Ling Wang, Xi Yang, Zhiping Zhang, Mengqiang Wu, Yujie Chang, Yacheng Yang, Linan Sun, Sirui Liu, Rongyao Zhu, Haowen Zheng, Xinyu Dai, Xiaohua Zhang, Chunhua Jiang, Zhuangzhi Zhu, Yuchen Zhang, Dongzhou Liu","doi":"10.1021/acs.jmedchem.4c01906","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01906","url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound <b>DD205-291</b> with high selectivity and potency. <b>DD205-291</b> showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with other inhibitors, <b>DD205-291</b> exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of <b>DD205-291</b> at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, <b>DD205-291</b> exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that <b>DD205-291</b> is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489088","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}
Jihee Kang, Hye-Yoon Jeon, Jieon Lee, Seri Bae, Ga Young Park, Kyoung-jin Min, Jeongmin Joo, Ah-Jun Lee, Hyo-Ji Kim, Chun Young Im, Eun-Bin Kim, Ji Hun Lee, Ji Sun Hwang, Seungju Lee, Jee-Young Lee, Pauline Navals, Jeffrey W. Keillor, Kwon-Soo Ha, Minsoo Song
{"title":"Structurally Minimalized and Druglike TGase2 Inhibitors Based on 7-Aminoquinoline-5,8-dione Scaffolds for the Treatment of Diabetic Retinopathy","authors":"Jihee Kang, Hye-Yoon Jeon, Jieon Lee, Seri Bae, Ga Young Park, Kyoung-jin Min, Jeongmin Joo, Ah-Jun Lee, Hyo-Ji Kim, Chun Young Im, Eun-Bin Kim, Ji Hun Lee, Ji Sun Hwang, Seungju Lee, Jee-Young Lee, Pauline Navals, Jeffrey W. Keillor, Kwon-Soo Ha, Minsoo Song","doi":"10.1021/acs.jmedchem.4c02081","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02081","url":null,"abstract":"Diabetic retinopathy is a disease that can cause vision loss leading to blindness in people with diabetes. Improved methods to treat and prevent vision loss in diabetic patients are in high demand owing to limited current treatment procedures. Herein, we report a new class of transglutaminase 2 (TGase2) inhibitors for the treatment of diabetic retinopathy based on 7-aminoquinoline-5,8-dione derivatives. 7-Amino-2-phenylquinoline-5,8-dione <b>11</b> and 7-amino-2-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}quinoline-5,8-dione <b>23</b> exhibited potent inhibitory activities against TGase2 in a fibrinogen array-based on-chip TGase2 activity assay and in an in situ assay in human retinal microvascular endothelial cells, with IC<sub>50</sub> values of 5.88 and 1.12 μM in vitro, and 0.09 and 0.07 μM in situ, respectively. Pharmacokinetically favorable 7-amino-2-{4-[(1-isopropylpiperidin-4-yl)oxy] phenyl}quinoline-5,8-dione <b>22</b> inhibited vascular leakage in the retinas of streptozotocin-induced diabetic mice via oral administration. Results from the AL5 kinetic assay and a molecular docking study suggest that the inhibitors may bind to TGase2 remote from the active site.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489092","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}
Xianyou Peng, Shanchun Guo, Shilong Zheng, Ahamed Hossain, Changde Zhang, Madhusoodanan Mottamal, Elena Skripnikova, Peng Ma, Kindy Martinez-Carter, Qiang Zhang, Faisal Abedin, Thomas Huckaba, Guangdi Wang
{"title":"Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations.","authors":"Xianyou Peng, Shanchun Guo, Shilong Zheng, Ahamed Hossain, Changde Zhang, Madhusoodanan Mottamal, Elena Skripnikova, Peng Ma, Kindy Martinez-Carter, Qiang Zhang, Faisal Abedin, Thomas Huckaba, Guangdi Wang","doi":"10.1021/acs.jmedchem.4c01205","DOIUrl":"10.1021/acs.jmedchem.4c01205","url":null,"abstract":"<p><p>The development of therapeutic resistance in the majority of patients limits the long-term benefit of ROS1 inhibitor treatment. On-target mutations of the ROS1 kinase domain confer resistance to crizotinib and lorlatinib in more than one-third of acquired resistance cases with no current effective treatment option. As an alternative to stoichiometric inhibition, proteolytic degradation of ROS1 could provide an effective tool to combat resistance generated by these mutations. Our study has identified a potent, orally active ROS1 degrader with an excellent pharmacokinetics profile. The degrader can effectively inhibit ROS1-dependent cell proliferation and tumor growth by degrading the ROS1 kinase, thereby eliminating the active phospho-ROS1. More importantly, the degradation-based therapeutic modality can overcome on-target mutation resistance to tyrosine kinase inhibitors by efficient degradation of the mutated kinase to achieve greater potency than inhibition.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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