Boheng Wan, Li Liang, Kaihong Zhong, Yiran Ma, Hui Wang, Ziang Wang, Shilong Sun, Tao Lu, Yadong Chen, Yong Zhu
{"title":"结构导向优化2-氨基喹唑啉类造血祖激酶1抑制剂提高口服生物利用度和协同抗肿瘤免疫","authors":"Boheng Wan, Li Liang, Kaihong Zhong, Yiran Ma, Hui Wang, Ziang Wang, Shilong Sun, Tao Lu, Yadong Chen, Yong Zhu","doi":"10.1021/acs.jmedchem.5c00762","DOIUrl":null,"url":null,"abstract":"Hematopoietic progenitor kinase 1 (HPK1), a pivotal T-cell immunity suppressor, offers transformative potential to overcome immune checkpoint resistance, yet existing inhibitors fail to balance potency, selectivity, and pharmacokinetics. We developed a spatially resolved strategy within a unified chemical framework of our 2-aminoquinazoline core, integrating (1) high-affinity engagement of the HPK1 hinge-region subpocket (Leu23/Phe93/Gly95) through bidentate hydrogen bonding and hydrophobic packing with (2) strategic occupation of a solvent-exposed allosteric site to sterically block CYP3A4/2C9/2D6-mediated oxidative metabolism. Optimized compound <b>39</b> demonstrated subnanomolar binding affinity (IC<sub>50</sub> = 0.70 nM) with moderate selectivity, combined with high metabolic stability in human liver microsomes (CL<sub>int</sub> < 1 mL/min/kg) and favorable oral bioavailability (>100%) in mice. In CT26 models, compound <b>39</b> synergized with anti-PD-1 (60% tumor growth inhibition) by expanding IFN-γ<sup>+</sup>CD8<sup>+</sup> tumor-infiltrating lymphocytes (7-fold) and enhancing splenic IFN-γ production (3-fold). This work validates 2-aminoquinazolines as a novel HPK1 chemotype addressing metabolic instability─a key hurdle in kinase drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure-Guided Optimization of 2-Aminoquinazoline Hematopoietic Progenitor Kinase 1 Inhibitors for Improved Oral Bioavailability and Synergistic Antitumor Immunity\",\"authors\":\"Boheng Wan, Li Liang, Kaihong Zhong, Yiran Ma, Hui Wang, Ziang Wang, Shilong Sun, Tao Lu, Yadong Chen, Yong Zhu\",\"doi\":\"10.1021/acs.jmedchem.5c00762\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Hematopoietic progenitor kinase 1 (HPK1), a pivotal T-cell immunity suppressor, offers transformative potential to overcome immune checkpoint resistance, yet existing inhibitors fail to balance potency, selectivity, and pharmacokinetics. We developed a spatially resolved strategy within a unified chemical framework of our 2-aminoquinazoline core, integrating (1) high-affinity engagement of the HPK1 hinge-region subpocket (Leu23/Phe93/Gly95) through bidentate hydrogen bonding and hydrophobic packing with (2) strategic occupation of a solvent-exposed allosteric site to sterically block CYP3A4/2C9/2D6-mediated oxidative metabolism. Optimized compound <b>39</b> demonstrated subnanomolar binding affinity (IC<sub>50</sub> = 0.70 nM) with moderate selectivity, combined with high metabolic stability in human liver microsomes (CL<sub>int</sub> < 1 mL/min/kg) and favorable oral bioavailability (>100%) in mice. In CT26 models, compound <b>39</b> synergized with anti-PD-1 (60% tumor growth inhibition) by expanding IFN-γ<sup>+</sup>CD8<sup>+</sup> tumor-infiltrating lymphocytes (7-fold) and enhancing splenic IFN-γ production (3-fold). This work validates 2-aminoquinazolines as a novel HPK1 chemotype addressing metabolic instability─a key hurdle in kinase drug discovery.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"20 1\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-05-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.5c00762\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.5c00762","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Structure-Guided Optimization of 2-Aminoquinazoline Hematopoietic Progenitor Kinase 1 Inhibitors for Improved Oral Bioavailability and Synergistic Antitumor Immunity
Hematopoietic progenitor kinase 1 (HPK1), a pivotal T-cell immunity suppressor, offers transformative potential to overcome immune checkpoint resistance, yet existing inhibitors fail to balance potency, selectivity, and pharmacokinetics. We developed a spatially resolved strategy within a unified chemical framework of our 2-aminoquinazoline core, integrating (1) high-affinity engagement of the HPK1 hinge-region subpocket (Leu23/Phe93/Gly95) through bidentate hydrogen bonding and hydrophobic packing with (2) strategic occupation of a solvent-exposed allosteric site to sterically block CYP3A4/2C9/2D6-mediated oxidative metabolism. Optimized compound 39 demonstrated subnanomolar binding affinity (IC50 = 0.70 nM) with moderate selectivity, combined with high metabolic stability in human liver microsomes (CLint < 1 mL/min/kg) and favorable oral bioavailability (>100%) in mice. In CT26 models, compound 39 synergized with anti-PD-1 (60% tumor growth inhibition) by expanding IFN-γ+CD8+ tumor-infiltrating lymphocytes (7-fold) and enhancing splenic IFN-γ production (3-fold). This work validates 2-aminoquinazolines as a novel HPK1 chemotype addressing metabolic instability─a key hurdle in kinase drug discovery.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.