Chemical tools for modulating the fetal hemoglobin inducer BCL11A

Project Summary/Abstract Proximity-based protein modulators such as proteolysis targeting chimeras (PROTACs) and molecular glues represent a new therapeutic modality because they can, through proximity-induced protein depletion, ablate all functions of their targets. Because of their ability to target non-enzymatic proteins, these molecules

have been heralded as key to eliminating the “undruggable” human proteome. However, the transformational potential of this technology is limited by the necessity of drug-like ligands for target proteins, which are sometimes intrinsically disordered or do not possess small molecule binding pockets. One of these target proteins is

BCL11A, the transcriptional repressor of fetal hemoglobin and a validated target for the treatment of sickle cell disease and beta-thalassemia. This proposal focuses on the development of modulators for BCL11A to spur new therapeutics for these disorders. Sickle cell disease and beta-thalassemia are the most common genetic hematologic disorders, affecting

millions of people worldwide. In these diseases, oxygen transport to metabolizing tissues is impaired. This leads to anemia, chronic pain, cardiac and pulmonary issues, decreased liver and spleen functions, etc. Many patients require costly lifelong care. Extensive research has firmly established that fetal hemoglobin, an alternate form

that is predominantly expressed during development but is silenced in adults, offers protection to patients. Yet, few therapies exist to reactivate fetal hemoglobin. There is one FDA-approved drug, that although widely prescribed in the US, does not work in many patients. More recently, gene therapy targeting BCL11A, has

successfully increased fetal hemoglobin in patients by 3 to 4-fold. While exciting, this therapy is costly, complicated, and has limited access, resulting in only hundreds of patients undergoing these procedures globally. Because it also requires autologous transplantation of genetically modified cells following myeloablative

conditioning, it is restricted to severely ill patients who have access to advanced clinical care. Clearly, alternative therapies are needed. The research described here aims to leverage chemical biology advances to develop tools for proximity- based depletion of BCL11A. In proof-of-principle studies, we recently reported first-in-class degraders for

BCL11A (Shen et al., 2022; Yin et al., 2023) that deplete up to ~ 70% of cellular BCL11A. BCL11A loss led to a significant induction of fetal hemoglobin to levels that, if achieved in patients, will be curative for sickle cell disease and beta-thalassemia. The proposed work will build on this finding to further advance these degraders

into viable therapeutic leads. Such advancement will require extensive ligand optimization and the development of cell- and organ-specific delivery vehicles to negate hematopoietic stem cell mobilization and ex vivo treatment. Beyond sickle cell disease and beta-thalassemia, the proposed strategy can be used to similarly modulate other

intractable but disease relevant protein targets.