Note for: PARP1 Inhibitors: antitumor drug design_2014
Note for: PARP1
Inhibitors: antitumor drug design_2014
PMID: 26483957
Overview
PARP1
-
common nuclear protein (1-2 million molecules/cells)
-
sensor for DNA strand breaks
-
highly expression of PARP1 can be found in some cancers,
treatment-resistance of tumors
-
act as chemotherapy and radio-sensitizer
-
focus on
properties and feature of PARP1 inhibitors: clinical and preclinical levels
-
discuss on
problems -- > application of PARP1 inhibitors, possibility of developing new
PARP1 inhibitors -- > aim at DNA binding and transcriptional activity rather
than catalytic domain
Introduction
-
DNA
break
o
PARP1
recognize through Zn-finger
o
Transferring
ADP-ribose to related protein as well as PARP1
§ Downstream effect
·
Chromatin
decondensation
o
Removing
H1 linker histone
·
Recruiting
repair enzyme
-
Three
levels of damage
o
Mild
damage -- > activation of PARP1 -- > DNA repair
o
Stronger
damage -- > PARP1 -- > apoptosis
o
More
extensive damage -- > overreaction of PARP1 -- > cell necrosis
-
PARP1
and carcinogenesis (pro-tumor activites)
o
Loss
§ Interfere with DNA repair -- >
genome shuffling and chromosomal abnormalities -- > more mutagenesis
§ Inhibiting transcription of genes
related to DNA replication and cell cycle regulation
-
PARP1
and cancer state
o
Gain
§ Prognosis -- > poor survival
§ More aggressive phenotype in breast
cancers
§ Tumor resistance to therapy
·
Facilitating
damaged DNA repair -- > improving genetic instability -- > characteristic
of transformed cells
History
of PARP1 inhibitor design
-
PARP1 used to enhance conventional therapy
o Chemosensitizer
o Radiosensitizer
-
First generation of PARP1 inhibitors
o Nicotinamide
analogues
§ Develop ~35
years ago (count up to 2020)
§ Based on
observation -- > nicotinamide (reaction’s product) -- > show moderate
inhibition
§ Benzamide --
> ineffective in practice
·
Cell culture -- > used as mM concentration
·
Non-specific action
·
Based line for further PARP1 development
o Nicotinamide/benzamide
-- > pharmacophore group
o 3AB
-
Second generation of PARP1 inhibitor is develop based on
quinazoline analogues
o More effective
and target specific
o PJ-34 -- >
further used in clinical trials
o Crystal
structure reveals carboxamide group forms several hydrogen bonds with Ser904-OG
and Gly863-N in catalytic domain of PARP1 -- > improve interaction between
heterocycle of 2nd inhibitor + PARP1
o Significance of
aromatic w-w interaction
between phenolic gr. of PARP1 inhibitor + phenolic gr. of Tyr907
o Crucial interactions which support specificity -- > hydrogen bond with Gly863, Ser904 and Glu988
-
Third generation of PARP1 inhibitor
o Benzimidazole-based
PARP1 inhibitor -- > 3rd gen
Mode of mechanism
-
PARP1 inhibition -- > failure of DNA repair
-
PARP1 binds to both SSB and DSB
-
Control several DNA repair pws
o BER
o NER
o MMR
o HR and NHEJ
HR defective which may contribute to PARP sensitivity
-
Mutation of BRCA1/2
o Other genes in
HR
§ RAD51
§ DSS1
§ RPA1
§ CHK1
-
PARP remains bound to damaged DNA -- > by the action
of inhibitor
-
Make it as obstacle for PARP-dependent repair enzymes or
BRCA1 to be recruited and fix the break
-
In HR defect cell, DSB -- > fix by NHEJ -- > NHEJ
is controlled by PARP1 through ADP-ribosylation on Ku70/80, DNAPK
o Prognostic
markers; mutation of
§ RAD51
§ NBS1
§ ATM
§ ATR
§ Chk1
§ Chk2
§ Rad54
§ FANCD2
§ FANCA
§ 53BP1
§ PALB2
§ FANCC
§ PTEN
PARP1+DNA methylation agents
-
DNA-methylating agents – dacarbazine (DTIC), temozolomide
(TMZ)
PARP1+TOPOI
-
Repair of TopoI-induced damage involves BER/SSB.
-
Thus, cell lacking key BER (i.e., XECC1) -- > hypersensitive
to camptothecin
-
PARP1 helps recruiting XRCC1 to TopoI-dependent DNA break
-- > recruit TDP1 -- > remove TopoI from DNA
-
PARP1 can interact with Topo-I -- > repairing
TopoI-dependent SSB
PARP1+Radiotherapy
-
Relied on the hypothesis -- > accumulation of SSB by
PARPi -- > causing more DSB during S-phase
Prospective for new inhibitory discovery
Problems
-
Compounds inhibiting NAD+ binding -- > low specificity
for PARP1 -- > blocking enzymatic pw. relating to NAD+ (which is cofactor
and relates to many cellular process, thus creating higher toxicity)
-
Enzymatic PARP1 inhibitors -- > activate viral
replication -- > thus this drug cannot use with patients infected with viruses,
ex. Human T-cell lymphotropic virus or Kaposi’s sarcoma-associated herpes virus
-
Long-term administration of PARP1 -- > still in
question on the side effects -- > example of toxicity -- > iniparib
(BSI-201)
-
Since PARP1 has many functional domains -- > DNA-binding
domain as well as transcriptional regulation have been proposed for another
drug design
o DNA binding
domain inhibitor has been recently developed
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