Molecular Glue Degraders for Treating Sickle Cell Disease

Discovery of WIZ as a Key Regulator of HbF Induction

Novartis researchers discovered that the WIZ (widely interspaced zinc finger motifs) transcription factor induces fetal hemoglobin (HbF), mitigating the severe complications associated with SCD. This discovery was made using a high-throughput screening assay developed with primary human CD34+ derived erythroblasts to measure proliferation, differentiation, and HbF expression.

Identification of Molecular Glues for Targeted Protein Degradation of WIZ

A molecular glue is a type of small-molecule drug that facilitates the interaction between two proteins, often leading to the degradation of one of the proteins by the cell’s natural protein disposal system, such as the ubiquitin-proteasome system. Unlike traditional drugs that inhibit the function of a protein by directly binding to it, molecular glues work by inducing a neomorphic interaction between two proteins that do not usually interact. This induced proximity can lead to the ubiquitination and subsequent degradation of a target protein by an E3 ubiquitin ligase complex, thereby modulating its levels and activity within the cell.

Novartis scientists identified molecular glues like dWIZ-1 and dWIZ-2 to target the WIZ transcription factor for degradation. These molecular glues recruit WIZ to the CRBN-DDB1 ubiquitin ligase complex, facilitating its ubiquitination and degradation. This approach allows for the selective removal of WIZ, leading to the induction of fetal hemoglobin (HbF), which is beneficial for the treatment of sickle cell disease.

Characteristics of WIZ-Targeting Molecular Glue Degrader

1. Pharmacokinetics

Researchers optimized the lead compound dWIZ-1 into dWIZ-2, which had improved pharmacokinetic properties and effectively degraded WIZ in human erythroblasts, inducing HbF without affecting cell differentiation or proliferation. dWIZ-2 induced HbF in a dose-dependent manner in erythroblasts from both healthy donors and sickle cell disease patients.

2. In Vivo Studies

In humanized mice, oral administration of dWIZ-2 significantly degraded WIZ and increased HbF-positive erythroblasts in the bone marrow. Similar effective results were observed in cynomolgus monkeys without impacting other blood parameters or causing toxicity.

3. Molecular Mechanisms

Genome-wide studies showed that WIZ binds to various chromatin sites and maintains repressive marks like H3K9me2. Treatment with dWIZ-2 reduced WIZ binding, decreased H3K9me2 levels, and increased the expression of genes involved in HbF regulation.

4. Safety Profile

In vivo studies in animal models revealed that WIZ degradation by dWIZ-2 was well-tolerated, with no significant adverse effects on body weight, blood counts, serum chemistries, or tissue histology.

Conclusion

By identifying WIZ as a novel repressor of HbF and developing molecular glues that facilitate targeted degradation of WIZ, the researchers have opened new therapeutic avenues that could provide safer and more effective treatments for SCD. The significance of this research lies in its potential to develop globally accessible, oral medications that could transform SCD management, particularly in underserved communities.

Reference

Ting, P. Y., Bradner, J. E., et al. (2024). A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction. Science, 385, 919–999.

Read our blog: Advancing PROTAC Therapeutics: Potency Assays for FDA Compliance