Targeted Protein Degradation as a Promising Tool for Epigenetic Upregulation of Fetal Hemoglobin

Abstract

The level of fetal hemoglobin (HbF) is an important disease modifier for β‐thalassemia and sickle cell disease patients. Indeed, genetic tinkering with the HbF repression machinery has demonstrated great potential for disease mitigation. Such genetic treatments are costly and the high incidence of β‐hemoglobinopathies in low‐income countries, therefore, calls for the development of affordable, off‐the‐shelf, oral treatments. The use of PROTAC (PRoteolysis TArgeting Chimeras) technology to influence the epigenetic mechanisms involved in HbF suppression may provide a solution. In this minireview, we briefly explain the HbF repression network highlighting the epigenetic factors that could be targeted for degradation by PROTACs. We hope that this review will inspire clinicians, molecular and chemical biologists to collaborate and contribute to this fascinating field, which should ultimately deliver drugs that reactivate HbF expression with high specificity and low toxicity.

Targeted protein degradation: A promise for undruggable proteins

“…Other proteins that regulate gene expression epigenetically, such as p300, PCAF/GCN5, SMACA2/4, Sirtuin 2, and EZH2 have also been degraded using PROTACs, showcasing the successful application of TPD in different protein classes as well as its ability to induce degradation of protein complexes (Bassi et al, 2018;Kargbo, 2020;Schiedel et al, 2018;Hsu et al, 2020;Vannam et al, 2021). Outside of these epigenetic regulators, Verheul et al (2020) proposed an array of key epigenetic targets that are amenable to PROTAC-mediated degradation. They proposed key gene expression regulators of fetal hemoglobin, such as histone demethylase LSD1 and nucleosome remodeling and deacetylase silencing complex, as a potential therapeutic approach to mitigate beta-thalassemia and sickle cell disease (Verheul et al, 2020).…”

“…Outside of these epigenetic regulators, Verheul et al (2020) proposed an array of key epigenetic targets that are amenable to PROTAC-mediated degradation. They proposed key gene expression regulators of fetal hemoglobin, such as histone demethylase LSD1 and nucleosome remodeling and deacetylase silencing complex, as a potential therapeutic approach to mitigate beta-thalassemia and sickle cell disease (Verheul et al, 2020).…”

A ubiquitin ligase toggles red cell differentiation

“…Suboptimal humoral response to vaccination has been reported in CLL. 2 In recent years, novel agents, namely inhibitors of BTK, phosphoinositide 3-kinases, or the antiapoptotic protein, B-cell lymphoma-2, have changed the treatment landscape…”

“…In addition, the proteasomal machinery can be hijacked to target selected proteins for degradation, thereby providing a powerful tool for research and drug development. 2 Xu et al have performed a CRISPR screen that inactivates the components of the protein degradation system. They observe that FBXO11 is required for terminal erythroid differentiation, but not for proliferation of progenitor cells.…”

In Silico Molecular Docking and Dynamics Simulation Analysis of Potential Histone Lysine Methyl Transferase Inhibitors for Managing β-Thalassemia

“…This suggests that higher HbF synthesis in RBCs could alleviate the progression of β-thalassemia. In such accordance, the therapeutics that could enhance HbF production have gained significant attention over the last few years, and reports that demonstrate the role of epigenetic regulators in HbF production have been well-documented [14,15]. Epigenetic regulators such as histone methyltransferases, which catalyze histone arginines and lysines with the help of S-adenosyl-methionine (SAM), play a vital role in DNA damage repairs, meiosis, germ cells, and embryonic development processes.…”