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Optimization of biliverdin IX? reductase redox inhibitors as novel reagents for enhancing platelet production

Award Number: R44HL150927
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Program Director/Principal Investigator (Last, First, Middle): NESBITT, Natasha M.. PROJECT SUMMARY/ABSTRACT This Phase II SBIR proposal will support our ongoing drug discovery program designed to develop and validate small molecule inhibitors of a novel drug target regulating platelet production in humans. The scope of work builds on strong genetic and biochemical evidence linking redox-dependent enzymatic activity of biliverdin IX¿ reductase (BLVRB) in a previously-uncharacterized regulatory pathway of megakaryocyte development and enhanced platelet production. In silico virtual screening with our novel scoring function led to the identification of ~20 compounds predicted to inhibit the redox activity of BLVRB. Biochemical and cell-based assays validated four of these compounds as potent inhibitors of the enzyme. A complementary crystallographic assay led to the identification of two additional compounds with increased potency towards BLVRB. We will employ medicinal and computational chemistry to optimize our hit compounds to develop lead compounds with improved potency and selectivity for BLVRB. These compounds will be further characterized using in vitro hematopoietic assays and follow up in vivo animal studies to show improved efficacy in comparison to our current hit compounds. Long-term success of this project is predicated on synergistic expertise in computational chemistry, platelet biochemistry, crystallography, and drug discovery. Successful completion of the research proposed in this grant has fundamental relevance to commercial development of a new class of platelet enhancing compounds functioning independently of the known thrombopoietin (TPO)/c-MPL receptor axis. Compound development and target validation provide a highly innovative strategy that would theoretically bypass toxicities associated with direct TPO/c-MPL agonists currently in clinical use (such as platelet activation, thromboembolic complications, and bone marrow fibrosis), while generating first-in-class redox inhibitors for further pre-clinical development. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


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: 2023 ( Subtotal = $613,208 )
2023	2023	BLOOD CELL TECHNOLOGIES LLC	9 SHIPYARD LN	SETAUKET	NY	11733	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	8/10/2023	NON-COMPETING CONTINUATION	$613,208
														Subtotal = $613,208

Issue Date FY: 2022 ( Subtotal = $763,993 )
2022	2022	BLOOD CELL TECHNOLOGIES LLC	9 SHIPYARD LN	SETAUKET	NY	11733	SUFFOLK	USA	Blood Diseases and Resources Research	001	2	6/9/2022	NON-COMPETING CONTINUATION	$763,993
2022	2021	BLOOD CELL TECHNOLOGIES LLC	9 SHIPYARD LN	SETAUKET	NY	11733	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	10/19/2021	NEW	$0
														Subtotal = $763,993

Issue Date FY: 2021 ( Subtotal = $690,965 )
2021	2021	BLOOD CELL TECHNOLOGIES LLC	9 SHIPYARD LN	SETAUKET	NY	11733	SUFFOLK	USA	Blood Diseases and Resources Research	000	1	8/6/2021	NEW	$690,965
														Subtotal = $690,965

Grand Total All Awards = $2,068,166

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Optimization of biliverdin IX? reductase redox inhibitors as novel reagents for enhancing platelet production

Award Number: R44HL150927

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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