# Development of novel fetal hemoglobin inducers using targeted protein degradation

> **NIH NIH F30** · YALE UNIVERSITY · 2024 · $33,892

## Abstract

The major -hemoglobinopathies, sickle cell disease (SCD) and -thalassemia, are two of the most common
monogenetic diseases. -thalassemia describes a heterogenous set of mutations, insertions, deletions, or
substitutions of the -globin gene, HBB, that result in no or decreased -globin synthesis. SCD on the other hand
is an autosomal recessive disorder that has a well-defined missense point mutation in the HBB gene, that
changes a glutamic acid to valine residue at the sixth position in the polypeptide sequence. This mutation causes
adult erythroid cells to express s-globin and synthesize an abnormal form of hemoglobin, HbS, that is prone to
polymerizing. Patients with -hemoglobinopathies cannot synthesize normal -globin, and thus cannot form
normally functioning adult hemoglobin, HbA, the predominant form in mature erythroid cells. Elevating levels of
fetal hemoglobin, HbF, in patients with -hemoglobinopathies can alleviate clinical symptoms. Compared to HbA,
which is composed of globin subunits 22, HbF is composed of 22 subunits. After birth, hematopoiesis shifts
from fetal hemoglobin expression in fetal liver to the bone marrow where adult erythrocytes are produced and
express adult hemoglobin. The transition from fetal to adult hemoglobin, from -globin to -globin expression,
requires several critical transcription factors (TFs), namely BCL11A and ZBTB7A, that recruit the Nucleosome
Remodeling and Deacetylase, NuRD, complex, and its catalytic component, CHD4, to the globin locus and
repress -globin expression. A third TF, ZNF410, was recently found to be a unique activator of CHD4
expression. CRISPR/Cas9 knockout or shRNA knockdown of each of these three TFs induces HbF expression,
and targeted therapies against these factors might offer a new therapeutic avenue for -hemoglobinopathies.
Immunomodulatory drugs (IMiDs) have been shown to recruit Cys2-His2 zinc-finger (C2H2-ZF) TFs to cereblon,
the substrate recognition component for the Cullin-4 E3 ubiquitin ligase (CRL4) complex, for targeted protein
degradation. The three TFs of interest all contain various numbers of tandem C2H2-ZF domains, and therefore,
I hypothesize that IMiD-induced targeted protein degradation of one or a combination of BCL11A,
ZBTB7A, or ZNF410, will lead to reactivation of the -globin gene and increase levels of HbF. Using a 1122
compound IMiD library built by the Crews lab, Aim 1 will determine which compounds from the library can serve
as lead hit compounds that will be optimized by iterative rounds of structure-activity relationship studies and
characterized in cellulo for target TF degradation. Aim 2 will examine the ability of these optimized compounds
to reactivate -globin expression and induce HbF synthesis in HUDEP-2 and primary erythroid progenitor cells.
Completion of this proposal will provide the preclinical framework to assess the therapeutic potential of targeted
protein degradation against TFs critical in the -globin to -globin switch ...

## Key facts

- **NIH application ID:** 10843746
- **Project number:** 5F30HL164007-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sijin Zheng
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $33,892
- **Award type:** 5
- **Project period:** 2023-04-16 → 2026-04-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843746

## Citation

> US National Institutes of Health, RePORTER application 10843746, Development of novel fetal hemoglobin inducers using targeted protein degradation (5F30HL164007-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10843746. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*