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Development of PARP-Isoform Selective Inhibitory Chemical Probes

Award Number: SC3GM131971
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Development of PARP-Isoform Selective Inhibitory Chemical Probes - Project Summary/Abstract The development of highly isoform-selective poly(ADP-ribose) polymerase (PARP) biochemical probes will fill crucial knowledge gaps that exist in our understanding of biological functions of PARP enzymes. PARPs are a family of nuclear enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) of substrate proteins such as histones. PARylation facilitates recruitment of DNA repair proteins. Consequently, PARP inhibitors (PARPi) are developed as a novel class of anticancer drugs that are used as single agents to treat BRCA-deficient tumors and as combination therapy with DNA damaging agents. The PARP superfamily is comprised of 17 members. Clinical PARPi are often associated with promiscuous inhibition of both PARP-1 and PARP-2 and some of them even inhibit other PARPs. This becomes a potential cause for their off-target hematologic toxicity. Due to non- specific targeting of multiple PARP-isoforms by currently known PARPi, a thorough interpretation of their pharmacological/clinical profiles has become highly complex. Further it was shown that PARP-1 inhibition alone is sufficient to repress the growth of MDA-MB-436 tumor xenograft. Depletion of both PARP-1 and PARP-2 led to embryonic lethality and aggressive T-cell lymphomas. One of the challenges impeding evaluation of PARP- isoform specific molecular interaction landscape in cellular context is the lack of potent and highly PARP-isoform selective chemical probes. Therefore, development of highly isoform selective PARP inhibitory probes is urgently needed. Weplan to address this by developing isoform-selective and potentially non-toxic novel PARP inhibitory chemical probes that will allow interrogation of changes in downstream signaling events of individual PARPs at a molecular level. The probes generated herein will also serve as template for the next generation preclinical agents. We will apply highly potent and novel set of UTT-lead compounds to develop exquisitely PARP-isoform selective chemical probes that will facilitate our understanding of biological functions of individual PARPs in both normal and diseased cells. As a proof-of-concept, we have synthesized and characterized several PARPi with nanomolar potency against both PARP-1 and PARP-2, with ~30-fold higher preference toward PARP-2. Based on this scientific premise and preliminary data, we propose the following specific aims: (A) to identify PARP-1 and PARP-2 selective biochemical probes; (B) to conduct in vitro PARP enzyme assays and isoform selectivity screening, and (C) to evaluate cytotoxicity of an isoform selective best PARPi in CAPAN-1 (BRCA2-/- and BRCA2cor) and SUM149 (BRCA1-/- and BRCA1cor) cells. These studies are expected to expand our knowledge on the impact of inhibiting a specific PARP-isoform by developed PARP chemical probes. By the end of the grant project period, we will be poised to evaluate cell-active and highly PARP-selective chemical probes in high value cell-based experiments. Subsequently, we plan to investigate PARP-isoform specific downstream signaling events, identification of new PARylated substrate proteins, on-target engagement and phenotypic change, and to validate if other PARPs are viable pharmacological targets.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$21,214 )
2025	2022	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PKWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	4	1/30/2025	NON-COMPETING CONTINUATION	-$21,214
														Subtotal = -$21,214

Issue Date FY: 2022 ( Subtotal = $123,000 )
2022	2022	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	4	6/27/2022	NON-COMPETING CONTINUATION	$123,000
														Subtotal = $123,000

Issue Date FY: 2021 ( Subtotal = $123,000 )
2021	2021	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	3	6/24/2021	NON-COMPETING CONTINUATION	$123,000
														Subtotal = $123,000

Issue Date FY: 2020 ( Subtotal = $123,000 )
2020	2020	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	2	5/26/2020	NON-COMPETING CONTINUATION	$123,000
														Subtotal = $123,000

Issue Date FY: 2019 ( Subtotal = $123,000 )
2019	2019	ST JOHN'S UNIVERSITY, NEW YORK	8000 UTOPIA PWY	JAMAICA	NY	11439	QUEENS	USA	Biomedical Research and Research Training	000	1	7/3/2019	NEW	$123,000
														Subtotal = $123,000

Grand Total All Awards = $470,786

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Development of PARP-Isoform Selective Inhibitory Chemical Probes

Award Number: SC3GM131971

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/03/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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