Kinase_Lecture_MedChem2

Kinase_Lecture_MedChem2

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Unformatted text preview: ker N N Me Me H N N H N O Imatinib N H N O CGP 53716 (IC50 0.1 µM) Piperazine N Spacer N • Piperazine increases ac4vity, selec4vity and water solubility • Spacer inserted to avoid aniline structure H N N N N Me H N N N • Increased ac4vity vs tyrosine kinases • No ac4vity against serine- threonine kinases IV (IC50 5 µM) H N O Schema5c of Type II inhibitors Ima4nib (Glivec or Gleevec) Binding interac4ons • Iden4fied from a crystal structure of an inhibitor- Abl kinase complex • Amide serves as an ‘anchoring group’ and orientates the molecule • Amide binds to Glu and Asp • Glu and Asp are important to the cataly4c mechanism Hydrophobic region Selectivity region 2 Glu Hydrophobic pocket Selectivity region 1 H O N O H N N O N MeS N O N H H H O Met N H O Thr Gatekeeper residue Me O N O2C Asp N Me Ima4nib (Glivec or Gleevec) Binding interac4ons ...
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This note was uploaded on 01/15/2014 for the course CHEM 167 taught by Professor Amaro during the Winter '13 term at UCSD.

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