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RAS

RAS. ?. RAL-GEF. PI3’K. RAF. proliferation. U0126 PD98059 PD184352 (CI-1040). MEK. AKT. ERK. proliferation survival. proliferation / differentiation survival migration. Structures of MEK Inhibitors. PD098059. U0126. PD184352 (CI-1040). PD0325901.

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RAS

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

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

  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 The Cell Cycle Mitosis: M phase Equal division of chromosomal content into two daughter cells

  5. 35 35 DMSO: G1: 67 S: 23 G2/M: 9 U0126: G1: 89 S: 4 G2/M: 5 Growth Curves: U0126 causes a reduc- tion in cell number. Cells accumulate in G1. DMSO: G1: 57 S: 16 G2/M: 26 U0126: G1: 70 S: 5 G2/M: 23 A. Mia PaCa-2 B. Panc-1 30 30 25 25 cells (x10-4/ml) 20 20 cells (x10-4/ml) 15 10 10 5 5 0 2 4 6 8 0 2 4 6 8 150 200 DMSO: G1: 48 S: 13 G2/M: 37 U0126: G1: 56 S: 8 G2/M: 35 DMSO: G1: 71 S: 10 G2/M: 18 U0126: G1: 80 S: 5 G2/M: 13 D. HPAF II C. CFPAC-1 days days 150 100 cells (x10-4/ml) cells (x10-4/ml) 100 50 50 0 0 0 2 4 6 8 0 2 4 6 8 80 200 DMSO: G1: 54 S: 21 G2/M: 25 U0126: G1: 73 S: 7 G2/M: 17 DMSO: G1: 52 S: 29 G2/M: 14 U0126: G1: 74 S: 14 G2/M: 7 E. Capan-2 F. MPanc-96 days days 60 150 cells (x10-4/ml) cells (x10-4/ml) 40 100 50 20 0 0 4 6 8 0 2 0 2 4 6 8 35 500 DMSO: G1: 58 S: 19 G2/M: 22 U0126: G1: 67 S: 14 G2/M: 18 H. BxPC-3 DMSO: G1: 51 S: 13 G2/M:35 U0126: G1: 65 S: 9 G2/M:27 G. Hs 766 T days days 30 400 25 300 cells (x10-4/ml) cells (x10-4/ml) 20 200 15 100 10 0 5 0 2 4 6 8 0 2 4 6 8 days days

  6. Enzyme catalysis: What are enzymes really doing?

  7. Enzyme kinetics (Michaelis Menten) Km: Michaelis constant k1, k-1, k2: rate constants for the individual steps

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

  9. Enzyme inhibition: competitive vs noncompetitive

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