Investor Presentaiton
30
PARG Inhibition is Synthetic Lethal with HRD
Novel, Mechanistically-Differentiated Target in a Clinically Validated Pathway
PARG Activity is required to resolve DNA Repair
PARG Inhibition is Mechanistically Distinct from PARPI
Replication Stress
DNA Damage
(SS break)
PARP Binding
PAR Chain Synthesis
(poly-ADP ribose)
Mechanisms of Tolerance
Fork
remodelling
vs
Re-priming
and TLS
PARP
trapping
PAR Chain Hydrolysis
(mediated by PARG)
T
IDE161
(PARGI)
4
DNA Damage Repair Proteins
(Recruited by PAR Chain Template)
PARP and PARG inhibitors have
distinct MOA and efficacy profiles
PARGI
ā
Fork Reversal
Fork
Protection
RAD51
modulators
e.g. BRCA1
BRCA2
and Slowing
Cell Death
(Nucleolytic Degradation)
PARPI
ā
Unrestrained
Fork Progression
Gap tolerance
Run off
Re-priming
& DSBR
TLS HR
e.g. BRCA1
BRCA2
Cell Death
(ssDNA gaps + DSBs)
Cancer Research (Aug 2019), Cancer Research (Jul 2019), Cancer Cell (Mar 2019)
Pillay et al., Progress in Biophysics and Molecular Biology 2021; McDermott et al., Cancer Cell 2019;
Zeman and Cimprich, Nature Cell Biology 2014
PARG
IDEAVA
BIOSCIENCESView entire presentation