35/36 - Transferases Flashcards
Kinases are targetted by what drug?
& what cellular processes does it mediate?
GLEEVEC = IMATINIB
many diseases involve kinase action
Cancer / vascular disorders / inflammation
Signal Transduction
Transcription / Differentiation
Apoptosis
What type of ENZYME?
type of Transferase
Transfer a phosphoryl group
from ATP –> to an ALCOHOL
(Hydroxyl -side group of AA in protein)
KINASE
(phospho-transferase)
Targetted by:
Gleevec = Imatinib
for CML
Features of GLEEVEC
Inhibition of ABL
- *High Affinity** for the ABL tyrosine Kinase
- inactive against other types of kinases & most other tyr kinases*
Gleevec –> binds near the ACTIVATION LOOP
which controls most of the catalytic activity
&
binds to the INACTIVE FORM of ABL
locking it in inactive position
GLEEVEC = Imatinib
MoA
COMPETITIVE INHIBITOR
binds directly into the ATP binding site of:
BCR-ABL Kinase
specifically a distinctive INACTIVE conformation
of the activation loop
VVVVV
which prevents the overproliferation of CML
& signal transduction
Development of RESISTANCE
against GLEEVEC
Observed in <80% of patients in 2 years
Thr315 mutation
sacrifices a favorable H-bonding interaction
and imposes a unfavorable steric clash
due to bulky isoleucine side chain
this prevents GLEEVEC from efficiently binding to BCR-ABL
OTHER DRUGS
that may replace GLEEVEC
DASATINIB = Sprycel
NILOTINIB = Tasigna
PONATINIB = Inclusig
good for the Thr315 mutant
Why is personalized medicine DIFFICULT?
Gleevec is an
exception rather than the rule
- *Few diseases** result from ONE SINGLE GENETIC DEFECT
- unlike CML*
for the ones that do, it is uncommon for the exact same varient
to be present in most patients
Most concaers involve solid tumors
Mutations are most likely to result in
- LOSS OF FUNCTION*
- rather than a gain in function in BCR-ABL kinase*
- *easier to INHIBIT rather than RESTORE function**
What type of ENZYME?
- *Move** a functional group from
- *one molecule to another**
Ex.
Kinases
TRANSFERASE
ex.
Kinase
targetted by Gleevec = Imatinib
What type of Two-Substrate Enzyme Mechanism?
Proceed though a covalent enzyme intermediate
which in the cases of kinases,
would be a phosphoenzyme species
PING-PONG MECHANISM
does NOT form a ternary complex
Ponatinib
brand name / indication / MoA
- *INCLUSIG**
- *2nd generation** ABL tyrosine kinase inhibitor for CML
useful for the Thr315 MUTATION!
overcomes the steric hinderance (triple bond)
&
compensates for the loss of H-bond (loss in affinity)
but it does lose some of GLEEVEC’s SELECTIVITY
Genetics of CML
Chronic Myeloid Leukemia
gleevec = imatinib
CHROMOSOMAL TRANSLOCATION
2 different chromosomes SWAP their DNA
VVVVV
generating the PHILADELPHIA CHROMOSOME
& a fusion protein called BCR-ABL
ABL = normal tyrosine kinase that modulates signal transduction
BCR-ABL=mutated versionthat isconstituitively ON
Why is GLEEVEC the
“Poster-child for personalized medicine”?
Right drug -> Right Dose -> Right Patient -> Right Time
Gleevec targets a specific type of leukemia = CML
which is caused by a genetic abnormality
&
Knowledge of the type of mutation directs the drug choice
- *GLEEVEC**
- *Target / Indication**
IMATINIB
targets KINASE (protein kinase)
- *CML**
- *Chronic Myelogenous Leukemia**
How does Gleevec have the
SPECIFICITY to this one kinase?
ABL = tyrosine kinase
Gleevec binds to the ATP-binding site
BUT it can still have HIGH specificity by recognizing a:
Distinctive INACTIVE conformation
of the activation loop of ABL
Dasatinib
brand name and indication /Moa
- *SPRYCEL**
- *2nd Generation Abl Kinase inhibitor** –> CML
does NOT target the activation loop
so it is Ineffective for the Thr315 mutation
