GluBio Presented an Oral Report on Preclinical Data of a First-in-Class WIZ Molecular Glue Degrader at the Second Molecular Glue Drug Development Summit
January 31, 2024San Diego, California, Jan 31, 2024 - GluBio Therapeutics Inc., a clinical-stage, Molecular glue degrader (MGD)-focused biotech company, will share preclinical data on its self-developed, first-in-class WIZ-targeting molecular glue degrader in an oral presentation at the 2nd Molecular Glue Drug Development Summit (Boston, MA, 2024).
About the WIZ Molecular Glue Mechanism of Action
The transcription factor WIZ (Widely Interspaced Zinc Finger) is a key component of the G9a and GLP histone 3 (H3) methyltransferase complex. It mediates the binding of G9a/GLP to specific chromatin regions and induces mono- and di-methylation of histone H3 at lysine 9 (H3K9), thereby specifically repressing gene expression1. Literature reports indicated that in adult erythrocytes, reduced protein expression or inhibited enzymatic activity of G9a or GLP induces hypomethylation of histone H3 lysine 9 in the promoters of genes encoding γ- and β-like globin chains. This leads to increased expression of fetal hemoglobin (HbF) and decreased expression of hemoglobin A (HbA)2. The immunomodulatory drug pomalidomide is a molecular glue degrader that can induce high-level HbF expression during in vitro differentiation of adult erythroid cells, although its exact mechanism of action has not yet been fully elucidated3. Furthermore, pomalidomide, by binding to the CRBN E3 ligase, induces polyubiquitination and subsequent degradation of WIZ4. Based on the above, we hypothesize that pomalidomide likely upregulates HbF primarily by degrading WIZ.
The preclinical data for the WIZ molecular glue degrader presented by GluBio at the 2nd Molecular Glue Drug Development Summit demonstrate that the WIZ molecular glue degrader induces HbF expression to an extent comparable to the HbF induction achieved by suppressing WIZ or BCL11A gene expression using RNAi technology. Moreover, WIZ molecular glue degraders with higher activity and selectivity than pomalidomide induced HbF expression more effectively and specifically. They also markedly reduced sickling in reticulocytes derived from the in vitro differentiation of peripheral blood CD34+ hematopoietic stem cells from patients with sickle cell disease, without causing notable cytotoxicity or impairing cell proliferation or differentiation. Therefore, this class of small molecule WIZ molecular glue degraders represents a potential novel therapeutic approach for treating sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT).
About the Molecular Glue Drug Development Summit
The Molecular Glue Drug Development Summit is one of the premier annual global conferences dedicated to molecular glue drug R&D. The summit aims to unite large pharmaceutical companies, innovative biotech firms, and leading academic institutions to accelerate the discovery, validation, and clinical translation of novel, rationally designed molecular glue drugs. The latest summit was a three-day event held in Boston, USA, from January 31 to February 2, 2024 (Beijing Time).
About Sickle Cell Disease (SCD) and Transfusion-Dependent β-thalassemia (TDT)
Hemoglobin (Hb) is the oxygen-carrying protein in red blood cells, normally a tetramer composed of two α-like globin chains and two non-α-like (β, γ, δ, or ε) globin chains. In normal adults, the major hemoglobin is HbA (α2β2), accounting for over 90% of total Hb, followed by HbA2 (α2δ2, 2-3%), and HbF (α2γ2, <2%). Infants and newborns have significantly higher HbF levels (~70% of total Hb) than adults, which gradually decrease to adult levels after one year of age.
SCD and TDT are blood disorders caused by inherited abnormalities in the β-like globin chain. The pathogenesis of SCD involves a point mutation in the β-globin gene, where glutamate at position 6 is replaced by valine, forming abnormal hemoglobin S (HbS). In the deoxygenated state, HbS polymerizes, forming insoluble fibers that distort the normally biconcave, disc-shaped red blood cells into sickle shapes. These sickled cells can impair blood flow, causing vaso-occlusion, which leads to painful crises and life-threatening damage to major organs and severe infections. TDT is a hereditary hemolytic anemia caused by reduced or absent synthesis of the β-globin chain, leading to insufficient HbA production. It is classified based on severity and transfusion dependence into thalassemia intermedia (TI) and thalassemia major (TM). Children with TDT typically present at 3-6 months (TM) or after 2 years (TI) of age, exhibiting moderate to severe hemolytic anemia and associated complications. Without transfusion therapy, most untreated children die from heart failure triggered by infection between ages 5-10. If transfusions are not accompanied by adequate iron chelation therapy, iron overload leads to organ damage and complications.
As one of the most common monogenic disorders globally, approximately 300,000 newborns are affected by SCD annually, with around 4.5 million people living with SCD worldwide and an average life expectancy of 40-60 years. According to the "China Thalassemia Blue Book (2020)", there are approximately 345 million thalassemia carriers globally, about 30 million carriers in China, and around 300,000 patients with severe and intermediate forms of thalassemia in China. The number of patients is increasing at an annual rate of about 10%, placing a heavy burden on affected families and healthcare systems and representing a significant global health concern.
Currently, approved drugs for treating SCD and/or TDT are very limited, primarily including small molecules like hydroxyurea, L-glutamine, and Voxelotor. In August 2022, the US FDA approved Zynteglo (generic name Beti-cel) developed by Bluebird Bio for treating transfusion-dependent β-thalassemia in adults and children, marking the first ex vivo lentiviral vector gene therapy approved for β-thalassemia patients, priced at $2.8 million. In December 2023, the US FDA approved Casgevy (generic name Exa-cel), developed by Vertex Pharmaceuticals and CRISPR Therapeutics, for treating patients aged 12 and older with recurrent vaso-occlusive crises due to SCD. This was the first FDA-approved CRISPR/Cas9-based gene-editing therapy. In January 2024, the FDA also approved Casgevy for treating transfusion-dependent β-thalassemia in patients aged 12 and older, priced at $2.2 million. Casgevy works by using gene editing to disrupt the erythroid-specific enhancer of the BCL11A gene, thereby suppressing BCL11A expression and inducing high-level expression of fetal hemoglobin HbF. This compensates for the defective HbS in SCD patients or the deficient HbA in TDT patients. Hydroxyurea acts through a downstream mechanism similar to that of Casgevy by inducing HbF expression, although its HbF induction levels and corresponding efficacy are considerably lower than Casgevy's. Therefore, novel small-molecule HbF inducers with efficacy equivalent or superior to Casgevy hold considerable therapeutic promise and market potential for SCD and TDT.
References
1.Bian et al. life (2015)4: e05606.
2.Krivega et al. Blood 2015) 126 (5):665–672.
3.Parseval et al. J Clin Invest (2008) 118(1):248-58.
4.Yu et al. oRxiv (2019) oi.org/10.1101/595389.