RAS PI3’K AKT RAL-GEF U0126 PD98059 PD184352 (CI-1040) proliferation survival proliferation / differentiation survival migration proliferation RAF MEK.

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Presentation transcript:

RAS PI3’K AKT RAL-GEF U0126 PD98059 PD (CI-1040) proliferation survival proliferation / differentiation survival migration proliferation RAF MEK ERK ?

PD U0126 PD (CI-1040) PD Structures of MEK Inhibitors

Model structure of MEK with bound inhibitor

Gap1: G1 phase Growth and preparation for DNA replication Synthesis: S phase Synthesis of DNA and centrioles Gap2: G2 phase Preparation for mitosis and cell division Mitosis: M phase Equal division of chromosomal content into two daughter cells The Cell Cycle

days Growth Curves: U0126 causes a reduc- tion in cell number. Cells accumulate in G1.

Enzyme catalysis: What are enzymes really doing?

Km: Michaelis constant k 1, k -1, k 2 : rate constants for the individual steps Enzyme kinetics (Michaelis Menten)

E E E E E E S S P P P P S S E E S S E E S S nI S S E E E E cI S S 1. Enzyme catalysis 2. Competitive inhibition 3. Noncompetitive inhibition

Enzyme inhibition: competitive vs noncompetitive

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