抗肿瘤药物的高通量筛选-生命科学试剂-MedChemExpress

1、Virtual Screening for Anti-tumor Drug Discovery虚拟筛选在抗肿瘤药物研发中的应用Master of Small Molecules您身边的抑制剂大师内容提要 HTS for Anti-tumor Chemicals 抗肿瘤药物的高通量筛选 VS for Anti-tumorchemicals 虚拟筛选的应用 ToolsforVS 虚拟筛选小工具Cancer 癌症人类健康杀手Cancer is one of humanitys greatest health challenges.Cancer is the first or second leadi

2、ng cause of death before the age of 70 years in 112 of 183countries and ranks third or fourth in a further 23 countries in 2019.Global cancer statistics 2020. /10.3322/caac.216603MCE Master of Small MoleculesChemicals in cancer treatment 抗肿瘤药物Chemotherapy and molecularly targeted therapy remain the

3、mainstay for the treatment of cancer Chemotherapy Alkylating agents: Ifosfamide, Arenobufagin, Etoposide Antimetabolite agents: 5-Fluorouracil, 6-Mercaptopurine, Carmofur Targeted therapy Ribociclib/Palbociclib/Abemaciclib:CDK, Cell Cycle/DNA Damage Tivozanib:VEGFR, Protein Tyrosine Kinase/RTK Venet

4、oclax:Bcl-2, Apoptosis/Autophagy Imatinib:BCR/ABL, v-Abl, PDGFR, tyrosine kinases Epacadostat: IDO1 Nolatrexed: TS, Cell CycleMolecules. 2020 Dec 7;25(23):5776.4MCE Master of Small MoleculesScreening Strategies 筛选策略 Target-Based Screening 基于已知靶点，筛选出的化合物机理清楚 筛选范围明确，得到候选化合物的概率更高 Phenotypic-Based Scree

5、ning 靶点未知，筛出的化合物的作用机理不清楚 筛选范围宽泛，需要用大量的化合物进行筛选Bioorg Med Chem. 2012 Mar 15;20(6):1922-8.5MCE Master of Small MoleculesDrug Development Process 药物研发流程Time-consuming （13-15）High-cost($2.6billion)LowSuccessRate(1/50001/10000)Nat Rev Drug Discov. 2008 Jul;7(7):591-6076MCE Master of Small MoleculesHTS Cas

6、e Study - Discovery of Epacadostat 依帕司他研发过程EpacadostatDiscovery ofIDO1 inhibitors（IncyteCorporation）Lead optimization Preclinical studys.clinical studys. high throughput screenof300000 compounds; Test absorbance of N- formlylkynurenine in 321nm. Get one lead compound with high potency and selectivit

7、y to IDO1, but with poor oralbioavailability. Synthesization of series ofderivatives(2000compounds). Improve the permeability and oral bioavailability. In vitro & in vivo Biological Assays Pharmacokinetic Assayscombination withantiPD1 mAb,pembrolizumab for thetreatment of patientswith melanoma . Molecularmodelling Enzyme KineticsACS Med. Chem. Lett. 2017, 8, 486-4917MCE Master of Small MoleculesVirtual Screening: Faster, Cheaper虚拟筛选in silico