Thatcher - TKI's Flashcards
Tyrosine Kinase Inhibitors
TKI
Transmembrane Enzyme Linked Receptors
-
Phosphrolation –> KINASE CASCADE
- Farely rapid but not as fast as gated channels
- AMPLIFICATION
- Non-covalent binding interactions using ATP binding site
Therapeutic Agents in Cancer Therapy
Antimetabolites
- INHIBIT purine/pyrimidine synthesis
-
INHIBIT the feeding for –> DNA synthesis
- = CYTOTOXIC APPROACH
- Often are Substrate Analogues
Therapeutic Agents in Cancer Therapy
Platinum-Based Agents
- DNA Damage
- PREVENT Transcription / Duplication
- Other DNA targeting agents:
- Alkylating Compounds
- DNA Intercalators
Therapeutic Agents in Cancer Therapy
Receptor Antagonist
Tyrosine Kinase Antagonist
Receptor Antagonist = HER2 / EGFR
- Bind to OUTSIDE or Inside of receptor
- –> STOPS CELL PROLIFERATION
Leukemia
Abnormal Proliferation of IMMATURE WBC’s
Hyperproliferation of WBC
- less RBC*
- Immature WBC = Myeloid or Lymphoid
Stages & Types of Leukemia
Acute
AML = Acute Myeloid Leukemia
ALL = Acute Lymphoblastic Leukemia
- Quick disease development
- Key Components are increased
- Clonal evolution might be present
- Associated w/
- Progressive leukocytosis
- Thrombocytosis
- Thrombocytopenia
- Basophilia
- Increased Blasts
- Splenomegaly / fever / Bone pain
Stages & Types of Leukemia
Chronic
CML = Chronic Myeloid Leukemia
CLL = Chronic Lymphoblastic Leukemia
- SLOW development
- Often asymptomatic
- disease is discovred after another disease / accident
- PREDOMINANCE of MATURE WBC
- High mortality
- Median Survival = 4-7 Years
CML
Chronic Myeloid Leukemia
- Originates @ Granulocyte Stem Cell precursors
- Progresses through 3 DISTINCT PHASES:
-
Chronic Phase
- 5-6 yrs
-
Advanced Phase
- 6-9 months
-
Blast Crisis
- 3-6 months SURVIVAL
-
Chronic Phase
Interferon-alpha based treatment
IFNa
early CML treatment
- Early 1980’s –> CML drug
- Increased survival vs conventional chemo.
- IFN’s naturally produced in immune system
- mechanism not fully understood
Philadelphia Chromosome
Short Chromosome 22
INDICATOR OF CML / ALL
- Normal = ABL on Chromosome 9
-
Philidephia = Translocation of ABL –> Chromosome 22
- = BCR/ABL
-
Chromosome 22 was shorter
- Bottom chunk swapped with chromosome 9
Chromosomal Rearrangements
Present in 70-90% of Leukemia Cases
- BCR/ABL = CML/ALL
ABL1
- = Protooncogene (might cause cancer)
- –> encodes for cytoplasmic & nuclear tyrosine kinase
-
Correlated in cell diffrentiation / division / adhesion / stress response
-
not only does PROLIFERATION cause cancer
- all these above factors also can
-
not only does PROLIFERATION cause cancer
- Negatively regulated by SH3 domain of the protein
BCR + SH3 Mutation
BCR/ABL
-
SH3 typicaly negatively regulates ABL
- withought sh3 –> ABL is permenantly Active
-
BCR –> keeps SH3 from doing so (SH3 domain is nonexistant)
- Insertion of BCR –> Causes Leukemia
-
BCR + ABL = uncontrolled growth + proliferation in WBC
- became a target for treating CML
Imatinib
Gleevec
First Generation TKI
Selective INHIBITOR of ABL & BCR-ABL derivative
- effective in CML patients (mainly in chronic phase)
- also used in other cancers
- ALL
- GI stromal tumors
- also used in other cancers
- __before imatanib –> CML = death
Imatinib
MOA
-
Competitively binds to Active site of BCR-ABL
- –> inhibits the protein
- STOPS cell proliferation
CML
Mechanisms of Resistance to TKI’s
KINASE ADAPTING
- Kinase itself adapting to become resistant to inhibitor
-
target reactivation
- secondary genetic alterators
- activation of upstream effectors
-
target reactivation
- Activating downstream effectors
- Bypass of oncoprotein effector
Resistance Mechanisms against:
Antimetabolites
OVERexpression of DNA synthesis genes
DHFR & TYMS
compensate for killing the metabolites/nutrients (purines/pyrimidines)
overcome the diffeciency
Resistance Mechanisms against:
Plat-Based Agents
Enhancing DNA Repair
ERCC1 upregulated
Resistance Mechanisms against:
TKI’s
Altered Target Molecules
Receptor Mutations
Other Resistance Mechanisms
-
Altered Membrane Transport = DRUG EFFLUX
- upregulate MDR1
- Enzymatic Deactivation
-
Resisting drug-induced cell arrest/apoptosis
- down regulate TP53
Imatinib
1/2 Resistance
-
Primary Resistance
- Insufficient inhibition of BCR-ABL
- Individual variation in bone marrow
-
Secondary Resistance
-
POINT MUTATION in the BCR-ABL kinase domain
- –> effect imatinib binding
- OVERproduction of BCR-ABL
-
POINT MUTATION in the BCR-ABL kinase domain
- Rate of Relapse
- increases as it goes further in phases
- Highest relapse in Blast Crisis
Dasatinib
Second Generation TKI
- Developed by targeting the point mutation in Imatanib
-
Inhibits multiple oncogenic TKI’s
- BCR/ABL & SRC family kinases
- secondary resistance can still occur
Nilotinib
Second Generation TKI
-
Developed based on crystal structure of ABL-Imatinib complex
- –> combat resistance
-
Specific Inhibitor of BCR/ABL (unlike Dasatinib)
-
NOT AS POTENT AS DASATINIB
- BUT IS MORE SPECIFIC
-
NOT AS POTENT AS DASATINIB
- Resistance keeps occuring –> more drugs needed
-
”Me-Too Drug”
- almost the same drug as imatinib but is needed for function against resistance
Nilotinib Vs Dasatinib Vs Imatanib
Specificity DOES NOT indicate more Potent
Though Nilotinib is more SPECIFIC than Dasatanib
it is NOT more Potent
- POTENCY:
- Dasatinib > Nilotinib > Imatinib
- Specificity:
- Nilotinib > Dasatinib > Imatinib
