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MedChem Final > Thatcher - TKI's > Flashcards

Thatcher - TKI's Flashcards

1
Q

Tyrosine Kinase Inhibitors

TKI

A

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
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2
Q

Therapeutic Agents in Cancer Therapy

Antimetabolites

A
  • INHIBIT purine/pyrimidine synthesis
  • INHIBIT the feeding for –> DNA synthesis
    • ​= CYTOTOXIC APPROACH
  • Often are Substrate Analogues
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3
Q

​Therapeutic Agents in Cancer Therapy

Platinum-Based Agents

A
  • DNA Damage
  • PREVENT Transcription / Duplication
  • Other DNA targeting agents:
    • Alkylating Compounds
    • DNA Intercalators
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4
Q

​Therapeutic Agents in Cancer Therapy

Receptor Antagonist

Tyrosine Kinase Antagonist

A

Receptor Antagonist = HER2 / EGFR

  • Bind to OUTSIDE or Inside of receptor
    • –> STOPS CELL PROLIFERATION
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5
Q

Leukemia

A

Abnormal Proliferation of IMMATURE WBC’s

Hyperproliferation of WBC

  • less RBC*
  • Immature WBC = Myeloid or Lymphoid
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6
Q

Stages & Types of Leukemia

Acute

A

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
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7
Q

Stages & Types of Leukemia

Chronic

A

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
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8
Q

CML

Chronic Myeloid Leukemia

A
  • 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
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9
Q

Interferon-alpha based treatment

IFNa

A

early CML treatment

  • Early 1980’s –> CML drug
    • Increased survival vs conventional chemo.
  • IFN’s naturally produced in immune system
    • mechanism not fully understood
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10
Q

Philadelphia Chromosome

A

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
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11
Q

Chromosomal Rearrangements

A

Present in 70-90% of Leukemia Cases

  • BCR/ABL = CML/ALL
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12
Q

ABL1

A
  • = 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
  • Negatively regulated by SH3 domain of the protein
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13
Q

BCR + SH3 Mutation

BCR/ABL

A
  • ​​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
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14
Q

Imatinib

Gleevec

A

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
  • _​_before imatanib –> CML = death
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15
Q

Imatinib

MOA

A
  • Competitively binds to Active site of BCR-ABL
    • –> inhibits the protein
    • STOPS cell proliferation
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16
Q

CML

Mechanisms of Resistance to TKI’s

A

KINASE ADAPTING

  • Kinase itself adapting to become resistant to inhibitor
    • ​target reactivation
      • ​secondary genetic alterators
      • activation of upstream effectors
  • Activating downstream effectors
  • Bypass of oncoprotein effector
17
Q

Resistance Mechanisms against:

Antimetabolites

A

OVERexpression of DNA synthesis genes

DHFR & TYMS

compensate for killing the metabolites/nutrients (purines/pyrimidines)

overcome the diffeciency

18
Q

Resistance Mechanisms against:

Plat-Based Agents

A

Enhancing DNA Repair

ERCC1 upregulated

19
Q

Resistance Mechanisms against:

TKI’s

A

Altered Target Molecules

Receptor Mutations

20
Q

Other Resistance Mechanisms

A
  • Altered Membrane Transport = DRUG EFFLUX
    • ​upregulate MDR1
  • Enzymatic Deactivation
  • Resisting drug-induced cell arrest/apoptosis
    • ​down regulate TP53
21
Q

Imatinib

1/2 Resistance

A
  • 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
  • ​Rate of Relapse
    • ​increases as it goes further in phases
    • Highest relapse in Blast Crisis
22
Q

Dasatinib

A

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
23
Q

Nilotinib

A

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
  • ​Resistance keeps occuring –> more drugs needed
  • ​”Me-Too Drug”
    • ​almost the same drug as imatinib but is needed for function against resistance
24
Q

Nilotinib Vs Dasatinib Vs Imatanib

A

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

MedChem Final (8 decks)

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