PARP Inhibitors
Abstract
Poly (ADP-ribose) Polymerase1 (PARP1) is a member of 17 membered PARP family having diversified biological functions such as synthetic lethality, DNA repair, apoptosis, necrosis, histone binding etc.
It is chromatin bound nuclear activated by DNA Damage. It binds on single - double strand breaks ,does PARylation of target and starts repair mechanism.
FDA approved PARP1 inhibitors in markets
- Olaparib
- Rucaparib &
- Niraparib
And Drugs in late stage clinical trials
- Veliparib &
- Talazoparib
all of this these molecules are non selective PARP1 inhibitors with concurrent inhibition of PARP2 with similar potency.
Classifed in Two main chemical classes
- NAD analogues
- non-NAD analogues
Introduction
PARP1 belongs to the ADP-ribosyl transferases (ART) family that uses NAD+ as a substrate,
cleave it catalytically and transfers the ADP-ribose moiety to acceptor proteins to create long chains of linear and/or branched poly (ADP-ribose) (PAR) as post-translational modification.
ATP, which acts as a local source of energy, is required by DNA ligase III, for completing the DNA repair process.
If ATP shortage occurs then PAR polymer might acts as a source of ATP by undergoing degradation mechanism of PAR by Poly ADP Ribose Glycohydrolase (PARG) and thus results into the generation of ADP-ribose units.
Damage in DNA can occur due to replication, exposure to exogenous toxins, ionizing radiations, ultraviolet radiation, enviromental factors, chemotherapy, cellular metabolite, radiotherapy, etc.
PARP enzyme family divided into 4 main groups
First group
- PARP1
- PARP2
- PARP3 that features a nuclear localization and get activated upon DNA damage.
Second Group
- PARP5 (known as Tankyrase,TNKS1)
- PARP5b (TNKS2) wich contain large ankyrin domains involved in promoting protein-protein intrections
Third Group
- PARP7
- PARP12
- PARP13 constitute the third group, having Zinc-finger domain involved in binding of RNA.
Fourth Group
- PARP9
- PARP14 &
- PARP15 having macrodomain folds which consist of functional modules of ADP-ribose-binding that promotes the association of these PARPs to the site pf poly amd mono(ADP-ribosyl)ation
Structural diffrences between enzymes of PARP family
Each enzymes differs in structure and function of the cell, this all gets activated by DNA strand breaks.
In PARP6 & PARP8,the gultamic acid residue appreas at a diffrent position,and replaced by aspartic acid in PARP15,but in case of PARP7,PARP9, PARP10, PARP13, and PARP16 nither glutamic acid and aspartic acid residues are present.
PARP9 and PARP13 lack NAD+ binding residue and catalytic glutamate,which makes them inactive
One Zinc fingure present in PARP7, PARP8, & PARP13 ,while Three Zinc fingure are present in PARP12
PARP9, encoded by B-aggressive lymphoma-1 (BAL-1) gene, has been discovered in patients with certain types of diffuse large B-cell lymphomas (DLBCL), which is expressed in the thymus and specific regions (neuroepithelium) of the brain and gut .
PARP14 is weakly expressed in the thymus during development.In adulthood,it essentially gets co-expressed with PARP9.
PARP10 and PARP15 consist of RNA Recognition Motif (RRM)
Structural organization in PARP1
DNA repair mechanism
There are 5 distinct DNA repair mechanism
- direct repair mechanism
- base excision repai (BER)
- mismatch repai (MMR)
- Double-strand break recombination repair
- Nucleotide excision repair (NER)
PARP plays a key part in the BER pathway
getting signal of DNA damage -> binds on single / double strand -> parylation of targated proteins (using NDA as substrate) like histone
if not repair -> single strand break converted to double strand break
BRACA1 and BRACA2 are key component of Homologous recombination (HR) pathway and so BRCAmutant tumors are inherently deficient in DNA repair
The order of PARP trapping potency of PARPiās from high to low is given as Talazoparib > Niraparib> Rucaparib > Olaparib > Veliparib
Apoptosis
Aptosis is a programmed cell death.
PARP1 by activation through binding to DNA strand break, contribute to cell death by depleating its pool of NAD+ and ATP
Three main stages of this ATP dependent apoptosis are inception, impact and execution
During execution, a group of enzymes called Caspases, specifically cleave the PARP1 and separates the DNA binding domain from the catalytic domain.This leads to conservation of cellular ATP for the apoptosis process
Keywords / Abbreviation
DBD - DNA Binding Domain
NLS - nuclear localization signal
BER- Base Excision Repair
BRCA- Breast Related Cancer Antigen
DSB - Double Strand Breaks;
HRR - Homologous Recombination Repair;
MDA-MB-231-M.D. Anderson Metastatic Breast -231(Human breast carcinoma cell line);
PARPis - PARP inhibitors;
PARylation - Poly ADP-Ribosylation;
DLBCL - diffuse large B-cell lymphomas
PARG - Poly (ADP) Ribose Glycohydrolase;
SNU-251 - Human ovarian carcinoma cell line
Nicotinamide adenine dinucleotide (NAD) is a key metabolite involved in a large array of cellular metabolic pathway.
PARylation is a post-translational protein modification catalysed by the poly(ADP-ribose) polymerase (PARP) enzymes.
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold.