title: Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
abstract: Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Hui-Jie
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Qi-Chao
authors.initials: QC
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.affiliation: State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D011725:Pyridines; D011743:Pyrimidines; C000620285:tetrahydropyrido(4,3-d)pyrimidine; D003577:Cytochrome P-450 Enzyme System