Maximizing cancer synthetic lethality using dual PI-3K/PARP inhibitors

PARP inhibitors PARPi are particularly efficacious in tumors deficient in the BRCA tumor suppressor
genes but of limited activity in BRCA competent tumors There is an unmet medical need to develop targeted
therapeutic agents which will augment PARPi activity for BRCA wild type cancers and to increase chemo
radiosensitivity in these malignancies BRCA proteins are essential components of the homologous
recombination HR double strand DNA repair mechanism PARPiandapos s synthetic lethality derives from preventing
the HR DNA double strand break DSB repair mechanism which the cancer cell cannot overcome resulting in
lethal DNA damage PARPi are selectively toxic to cells with BRCA deficiencies or other DNA repair
pathway mutations as found in some triple negative breast cancers A recent report demonstrated that PI
kinase PI K inhibition impairs BRCA expression and can sensitize BRCA proficient cancers to PARP
inhibition Hence our central hypothesis to be tested in this proposal is that a combination dual PI K
inhibitors PI Ki PARP inhibitor will attack the cancer cell s DNA repair mechanisms via at least two
orthogonal pathways and extend PARPi clinical activity beyond just those deficient in BRCA and or other
DNA repair defects An innovative component of our proposal is that we have developed in silico the first
small molecule inhibitory chemotype which inhibits both PI K and PARP activity simultaneously e g
SRX preliminary results We have demonstrated proof of concept that SRX augments cell
death following DNA damage Inhibits both targets DNA repair and PI K simultaneously in the same tumor
cell and displays less toxicity in normal cells compared with individual inhibitory chemotypes at equivalent
potency against targets The significance of our proposal lies in our capacity to provide an optimizable
promising single anticancer agent which will potently inhibit DNA repair via multiple orthogonal mechanisms
and chemo radiosensitive tumor cells to DNA damaging agents This proposal will evaluate this approach by
achieving the following aims setting the stage for phase II efforts to optimize the expected dual inhibitor lead
compound s to a clinical candidate Aim Task Develop a dual PI kinase PARP inhibitor Aim Task
Develop a predictive computational PARP model for the in silico docking of designed compounds
Approach Improve in silico PARP ligand fit parameters of our PARP model until a high PARP docking PARP
assay inhibition correlation is achieved Aim Task Determine therapeutic window for dual PI K PARP
inhibition Approach Compare toxicity towards neuronal cancer stem cells versus normal neuronal stem cells
NSCs when exposed to single PARP inhibitor or PI K inhibitor versus dual PARP PI K inhibition conditions
The significance of this research is it will greatly expand the reach of PARP inhibition into BRCA proficient
cancers This innovative approach attacks cancer using two distinct proven mechanisms with a single
compound challenging the one drug one target dogma The planned research is relevant to public health because data we and others have acquired
shows that our proposed development of a potent novel PI kinase PARP dual inhibitor to target
cancer cell DNA repair mechanisms Moreover the proposal is designed to produce a platform
technology for the development of dual small molecule inhibitors of PI K combined with
inhibitors of other targets thereby having a broad impact on public health Thus the proposed
research which will involve a close collaboration between academia and industry is relevant to
the part of the NIHandapos s mission that pertains to the development of new therapeutics able to
reduce the burden of human disability via improved treatment of adult and childhood cancer