Med Chem Antineoplastics

Front 1

Trastuzumab
(Herceptiin)

Back 1

-Monoclonial antibody that targets cancer cells overproducing HER2
-Used for Tx of breast cancer
-Approved in 1999

Front 2

Gleevec

Back 2

-1st small molecule drug
-Approved in 2001
-Tx of Chronic Myelogenous Leukemia (CML)

Front 3

Cancer Stats

Back 3

-1.4 Million Americans Diagnosed a year
-500,000 Americans die each year
-Breakdown:
1)30% from smoking
2)30% from dietary factors
3)15% from viruses
4)25% inherited/other factors
-Prostate/Breast has highest incidence (>30%)
-Lung as highest mortality rate (31% males, 27% females)

Front 4

How Does Cancer Occur?

Back 4

-Through mutations to DNA, cells accumulate damage
-Proteins which promote proliferation are switched on (oncogenes)
-Proteins that prevent tumor formation (tumor suppressor proteins) are switched off
-Can also occur via:
1)Abnormal signaling pathways
2)Insensitivity to growth inhibitory signals
3)Abnormalities in cell cycle regulation
4)Evasion of programmed cell death
5)Cell death processes are disabled (cell immortality)
6)Ability to develop new blood vessels
7)True invasion & metastasis

Front 5

Body's Defense Against Cancer

Back 5

1)Cell cycle checkpoints
2)DNA repair
3)Tumor Suppressor
4)Proapoptotic Proteins
5)Immune System
6)Apoptosis (Cell suicide) if none of the above detect damage

Front 6

Cellular Transformation

Back 6

-When a normal cell becomes a tumor cell after many mutations
-Causes rapid proliferation and immortality

Front 7

Eukaryotic Cell Cycle

Back 7

-Tightly regulated/coordinated series of events
-Controls cell growth/division
-Gap phases prepare cell for DNA synthesis (replication) and division (mitosis)
-Checkpoints allow for detection of problems and damage repair
-Cancer cells OFTEN BYPASS checkpoints

Front 8

Cyclin Dependent Kinases
(Molecular Switches for the Cell Cycle)

Back 8

-Kinases that when active promote cell cycle progression
-Control growth arrest or progression through production of cyclins (which activate CDKs)
-Natural CDK inhibitors turn off kinase activity and cause CELL CYCLE ARREST
-Tumors arise through OVERPRODUCTION of cyclins or MUTATIONS in CDK inhibitor genes
-Types of CDKs and cyclins:
1)CDK4,6;Cyclin D=G1
2)CDK2;Cyclin E=G1 to S
3)CDK2;Cyclin A=S
4)CDK1;Cyclin B=M

Front 9

Cell Cycle Checkpoints
G1 Phase

Back 9

Is the environment favorable?
Is the cell big enough?
Is DNA damaged?

Front 10

Cell Cycle Checkpoints
G2 Phase

Back 10

Is DNA damaged?
Is replication complete?

Front 11

Cell Cycle Checkpoints
M Phase

Back 11

Are chromosomes properly arranged?

Front 12

CDKs

Back 12

-Form multisubunit complexes:
1)ATP binding site
2)Catalytic subunit (CDK2)
3)Regulatory subunit (Cyclin A)
4)CDK inhibitory protein (P27)

Front 13

Signal Transduction Pathways Control CDKs

Back 13

-Growth factors stimulate EGF receptors which causes signal transduction which causes enzyme cascades to produce cyclins which activate and proliferate CDKs
-Anti growth factors stimulate TGF-B receptors which causes a signal transduction and enzyme cascades and produces CDK inhibitory proteins which cause CDK inhibition/arrest

Front 14

Apoptosis

Back 14

-Starts by DNA damage occurring which stimulates P53 which stimulates BAX
-Mitochondria membrane permeability altered, Cytochrome C released, activates Apoptosome, which activates Caspases, which results in Apoptosis

Front 15

Regulation of Apoptosis

Back 15

-Occurs through 4 pathways:
1)T-lymphocytes affecting granzymes
2)Low levels of growth factors stimulating EGF receptors
3)Death activator proteins stimulating tumor necrosis factor receptors
4)BCL-2 (antiapoptotic protein) binds to BAX (apoptotic protein) preventing it from acting on mitochondria so apoptosis doesnt occur

Front 16

Pathways of Apoptosis

Back 16

-Extrinsic Route
1)Factors outside cell trigger apoptosis (death activator proteins signaling)
2)Immune response identifies damaged cells, injects the granzyme and initiates apoptosis
-Intrinsic
1)Detection of DNA damage triggers P53 accumulation
2)Pro-apoptotic factors produced which induce release of Cytochrome C
3)Apoptosome activates Caspases which destroy cell components

Front 17

Balance of Apoptosis

Back 17

-Fine balance between Pro and Anti-Apoptotic factors
-Pro-Apoptotic Factors=BAX
-Anti-Apoptotic Factors=BCL-2
-Cancer cells tip the balance towards cell survival (Anti-apoptotic factor BCL-2)

Front 18

p53 Protein

Back 18

-Frequently mutated in human cancer
-Transcription factor that promotes expression of cell cycle inhibitors (proapoptotic proteins)
-If it is defective, no cell cycle inhibition and no apoptosis triggered
-DNA damage is not repaired and cells with mutations continue to proliferate
-p53 activity is very tightly controlled
-Responsible for maintaing genomic integrity

Front 19

Cancer Chemotherapy Agents

Back 19

-Targets DNA, pathways, and cellular structures common to normal and transformed (cancerous) cells
-Notorious for side effects: Narrow Therapeutic Index
-Kills many rapidly proliferating cell types leading to toxicities
-Dramatic increase over past 20 yrs in how tumor formation occurs
-Past 10 years, drugs target specific biological mechanisms that are deregulated in tumors
-Cancer is a chronic disease

Front 20

Classes of Antineoplastics

Back 20

-Alkylating agents
-Antimetabolites
-Topoisomerase inhibitors
-Antimicrotubular agents
-Hormone modulators
-Inhibition of signal transduction pathways
-Proteosome inhibitors
-Inhibition of angiogenesis
-TO COME: cell cycle modulators, antiapoptosis, inhibitors of protein folding pathways