Kinase_Lecture_MedChem2

With a glutamate residue ima4nib inhibits protein

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Unformatted text preview: d block access to ATP • Type II inhibitors act on the inac4ve conforma4on of the enzyme • Type II inhibitors bind to the enzyme and stabilise the inac4ve conforma4on • Type II inhibitors are likely to be more selec4ve Type I inhibitors Gefi4nib, erlo4nib, SU11248 and seliciclib Type II inhibitors Ima4nib, lapa4nib, sorafenib and vatalanib Abl and Src Src, Abl, and Bcr- Abl hOp://jkweb.mcb.berkeley.edu/external/research- in- progress/5- 3/signaling/abl_kinase.html Ima4nib (Glivec or Gleevec) N Me H N N N H N O N Me N Notes • First protein kinase inhibitor to reach the market • Selec4ve inhibitor for a hybrid tyrosine kinase (Bcr- Abl) • Bcr- Abl is ac4ve in certain tumour cells Ima4nib (Glivec or Gleevec) Lead compound Pyrimidine H Anilino substituent N N N I • Phenylaminopyrimidine structure • Iden4fied by random screening of compound libraries • Originally iden4fied as a PKC inhibitor • PKC is a serine- threonine kinase Ima4nib (Glivec or Gleevec) Drug design Pyridine N H N N N N N I H N 3' N II H N N N IV (IC50 5 µM) H N Amide Increased inhibi4on of PKC Inhibits tyrosine kinases as well O Ima4nib (Glivec or Gleevec) Drug design Conformational! bloc...
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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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