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

2. PD098059 U0126 PD184352 (CI-1040) PD0325901 Structures of MEK Inhibitors

3. Model structure of MEK with bound inhibitor

4. 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

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

6. Enzyme catalysis: What are enzymes really doing?

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

8. 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

9. Enzyme inhibition: competitive vs noncompetitive