# Optimization of biliverdin IXβ reductase redox inhibitors as novel reagents for enhancing platelet production

> **NIH NIH R44** · BLOOD CELL TECHNOLOGIES, LLC · 2022 · $763,993

## Abstract

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

## Key facts

- **NIH application ID:** 10463549
- **Project number:** 5R44HL150927-02
- **Recipient organization:** BLOOD CELL TECHNOLOGIES, LLC
- **Principal Investigator:** Natasha M. Nesbitt
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $763,993
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463549

## Citation

> US National Institutes of Health, RePORTER application 10463549, Optimization of biliverdin IXβ reductase redox inhibitors as novel reagents for enhancing platelet production (5R44HL150927-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463549. Licensed CC0.

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