改造天然产物bionmrlabustc.pptVIP

* 保泰松的代谢活化 6、幸运 结构解析错误 Penicillin Chlordiazepoxide (Roche) cisplatin carboplatin oxaliplatin lobaplatin More good luck: Target Library Synthesis Full screening Lipinskis RO5 Fragment grow, link and merge Fragments: Fragment-based Screening High Throughput Screening 102 ~104 RO3 compounds (~106 compounds, ~$$2M/Screening) Small is better (sample bigger chemical space, higher hit rate, higher Ligand Efficiency, less false positive results, more intuitive to medicinal chemists) 7、Fragment based lead discovery Fragment Library Target X-ray / NMR Structures b c a NMR Competitive Binding Experiment Evolution Validation Biacore HSQC *Hubbard et al (2007), Curr Topics Med Chem, 7, 1568 Biacore Fragment Based Lead Discovery Clinical candidates of fragment-derived compounds Compound Company Status Target Therapy areas Vemurafenib Plexxikon/Roche Phase IV B-RAF Melonoma (first FBDD drug on market, FDA approved in 2011) ABT-263 Abbott Genentech Phase II Bcl-xL Small-cell lung cancer, CML, Lymphoma, Hematological neoplasm Cancer ABT-869 Abbott Phase II VEGF and PDGF receptor tyrosine kinase family members Non-small-cell lung cancer, etc. AT-7519 Astex Phase II CDK family members Multiple myeloma cancer AT-9283 Astex Phase II Aurora kinase family members Flt3 tyrosine kinase, Jak2 tyrosine kinase Abl tyrosine kinase Hematological neoplasm Solid tumor Compound Company Status Target Therapy areas DG-051 deCODE Phase II Leukotriene A4 hydrolase Myocardial infarction PLX-204 Plexxikon Phase II PPAR alpha, delta, gamma Inflammatory disease Cardiovascular disease Non-insulin dependent diabetes LY-517717 Lilly Tularik Phase II Factor Xa Thrombosis NVP-AUY-922 Vernalis Novartis Phase II ATPase Hsp 90 Cancer Solid tumor ABT-518 Abbott Phase I Gelatinase Metalloprotease-2 Metalloprotease-9 Solid tumor IC-776 Lilly ICOS Phase I CD11a, ICAM Inflammatory disease, Psoriasis, Autoimmune disease AT-13387 Astex Phase I Hsp 90 Cancer Compound Company Status Target Therapy areas PLX-4032