Introduction to the Basics of Signal Transduction

1. Introduction to the Basics of Signal Transduction Mauricio Lema Medellín, Colombia

2. … Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados.

3. Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks

5. Growth factors Nutrients & O2 Hormones Cell-Cell inter.

6. Signal Transduction Signal transduction describes the process through which extracellular signaling molecules bind specific receptors on target cells, which consequently activate selected intracellular biochemical pathways

7. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

14. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

15. Kinases Post-translational modifications are key to signal transduction • Phospholylation of Ser / Thr / Tyr may TURN ON / OFF a specific protein • The balance of P / de-P will establish a response

17. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

23. Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors

25. Signal Transduction Pathways • “Growth Factor” pathways • Rb • c-myc • TGFB • Hypoxia pathway • mTOR • IGR • MET • VEGF • EGFR

30. Anti VEGF

32. PI3K inhibitors RAF inhibitors Temsirolimus / Everolimus

34. PI3K inhibitors Raf Inhibitors

35. mTOR inhibitors

39. Shc Grb2 PI3-K Sos-1 Ras AKT Raf MEKK-1 MEK mTOR MKK-7 ERK JNK Angiogenesis Metastasis Apoptosis Resistance Proliferation Signaling EGFR

40. VEGF ANGIOGENESIS PLC PLC PI3-K PI3-K FAK FAK Ras Ras P P P P PKC PKC IP3 IP3 AKT AKT Paxillin Paxillin MAPK MAPK Migration Migration Survival Survival Proliferation Proliferation ANGIOGENESIS VEGF Binding & Activation of VEGFR Endothelial-Cell activation

41. Let’s put it simple… Signal – Receptor interaction

42. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC

43. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb

44. Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb EFFECTOR TF – DNA interaction

45. Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks

46. Cyclin Dependent Kinases Inhibitor • SCH 727965 (J. Nemunaitis, P.ASCO 2009, Abstract 3535) • 0/43 Responses

47. Raf Kinase Inhibitor • XL-281 (GK Schwartz, P.ASCO 2009, Abstract 3513) • 1/30 PR • 12/30 SD HSP • Alvespimycin (SC Pacvev, P. ASCO 2009, 3534) • 2/25 PR • OGX-427 (SJ Hotter, P. ASCO 2009, 3506) • 5/34 SD

48. Akt inhibitor • MK-2206 (AW Tolcher, P.ASCO 2009, Abstract 3503) • 6/19 SD

49. PI3K inhibitors • XL-147 (G. Shapiro, P.ASCO 2009, Abstract 3500) • 6/39 SD • GDC-0941 (AJ Wagner, P.ASCO 2009, Abstract 3501) • 3/19 SD • XL-765 (P. LoRusso, P.ASCO 2009, Abstract 3502) • 5/34 SD • Enzastaurin (MA Carducci, P.ASCO 2009, Abstract 3517) • 9/43 PR (Con Bevacizumab)

50. IGF1R/Aurora/SRC inhibitor • XL 228 (DC. Smith, P.ASCO 2009, Abstract 3512) • 1/30 PR • 9/30 SD