抗腫瘤藥物的高通量篩選-生命科學(xué)試劑-MedChemExpress

1、Virtual Screening for Anti-tumor Drug Discovery虛擬篩選在抗腫瘤藥物研發(fā)中的應(yīng)用Master of Small Molecules您身邊的抑制劑大師內(nèi)容提要 HTS for Anti-tumor Chemicals 抗腫瘤藥物的高通量篩選 VS for Anti-tumorchemicals 虛擬篩選的應(yīng)用 ToolsforVS 虛擬篩選小工具Cancer 癌癥人類健康殺手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 抗腫瘤藥物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 篩選策略 Target-Based Screening 基于已知靶點(diǎn)，篩選出的化合物機(jī)理清楚 篩選范圍明確，得到候選化合物的概率更高 Phenotypic-Based Scree

5、ning 靶點(diǎn)未知，篩出的化合物的作用機(jī)理不清楚 篩選范圍寬泛，需要用大量的化合物進(jìn)行篩選Bioorg Med Chem. 2012 Mar 15;20(6):1922-8.5MCE Master of Small MoleculesDrug Development Process 藥物研發(fā)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 依帕司他研發(fā)過(guò)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虛擬篩選in silico