Kinase_Lecture_MedChem2

Inhibi4on of pkc inhibits tyrosine kinases as well o

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Unformatted text preview: 4nib analogs Drug Resistance •  Where might a drug resistance muta5on arise in the progression of cancer? –  Resistance muta5on can not break ATP/substrate binding or cataly5c machinery Kinase inhibitors: gefi4nib analogs drug- resistant muta5on Thr- to- Met in the binding site produces steric clash with the drug (modeled in b) Lapa4nib and Etlo4nib F O Aniline ring Aniline ring NH Cl NH 4 N O N N O HN SO2Me Quinazoline ring Lapa4nib Notes • 4- Anilinoquinazoline structures - compare gefi4nib • EGF- receptor kinase inhibitors N O Quinazoline ring Erlo4nib (Tarceva) IC50 2 nM OMe OMe Designing Selec5ve Kinase Inhibitors •  Ac5ve conforma5on of ATP binding pocket is too similar among protein kinases •  What are some alterna5ves? Designing Selec5ve Kinase Inhibitors •  Alterna5ves: –  Target inac5ve conforma5ons that might offer more selec5vity –  Target other sites where selec5vity and synergy with ac5ve site inhibitors might be achieved –  Case study: Bcr- Abl Type II Inhibitors Protein Kinase Inhibitors Notes • Type I inhibitors act on the ac4ve conforma4on of the enzyme • Type I inhibitors bind to the ATP binding site an...
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