# Identification of novel y-globin corepressors and advanced inhibitor development

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $500,270

## Abstract

Abstract:
The ultimate goal of this research is to provide safe, effective, accessible and durable disease modification for
sickle cell anemia (SCD) and β-thalassaemia (CA) that will improve multi-organ pathophysiology and reduce
early death. Incontrovertible data from both basic and clinical research studies over the past 40 years support
the premise that inducing fetal γ-globin (HBG) gene repression would be therapeutic in human patients. The
two specific aims of this proposal focus on the manipulation and specific targeting of the transcriptional
regulatory machinery that represses HBG genes during development. Our first aim is devoted to the discovery
and validation of new epigenetic modifying enzymes that elicit γ-globin repressive activity in adult erythroid
progenitor cells, and we describe several promising new candidate enzymes that we propose to investigate for
potential drug targeting. Our second aim is to refine structure-based inhibitors of the epigenetic modifying
enzyme LSD1 (KDM1a), which (we showed in a proof of concept study) could constitute an ideal target for
therapeutic intervention for the treatment of these diseases. Through structure-aided design coupled to
iterative enzyme inhibition and cell-based HbF induction assays, we are currently refining and testing fourth
and fifth generation inhibitors (designed at the University of Michigan). These compounds have evolved to the
point that they are proposed to be highly specific for LSD1 (with IC50s < 90 nM), are reversible, exhibit no
behavioral or cardiac side effects and can be orally administered. We have already developed LSD1 inhibitors
that were partially successful in preclinical animal studies, and here we propose to develop novel compounds
with minimal undesirable on target effects. We propose to follow up these preclinical studies, in collaboration
with investigators in project 2, by analysis of the effects of the best of these novel inhibitors in baboons, and if
those are successful, in collaboration with project 3, in human clinical trials. The projected impact for patients
suffering from β-globinopathies is that these proposed HbF-inducing therapies will be sufficiently efficacious to
counter the devastating complications of these diseases such as stroke and acute chest syndrome, and with
accessibility and safety parameters that will permit universal application as well as life-long use.

## Key facts

- **NIH application ID:** 9986893
- **Project number:** 5P01HL146372-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** James Douglas Engel
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,270
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986893

## Citation

> US National Institutes of Health, RePORTER application 9986893, Identification of novel y-globin corepressors and advanced inhibitor development (5P01HL146372-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986893. Licensed CC0.

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