ARP-49

ARP-49 is a cereblon-based targeted protein degrader (PROTAC) designed to induce fetal hemoglobin (HbF) for the treatment of hemoglobinopathies such as sickle cell disease and thalassemia. It functions by recruiting the cereblon (CRBN) E3 ubiquitin ligase to histone deacetylases 1 and 2 (HDAC1 and HDAC2), leading to their polyubiquitination and subsequent proteasomal degradation. ARP-49 demonstrates selectivity for HDAC1 degradation over HDAC2 and HDAC3. In preclinical models using HUDEP-2 cells, ARP-49 significantly increased HBG1/2 mRNA levels and the percentage of HbF-positive cells, showing superior potency compared to hydroxyurea. It was developed through a collaboration between the University of Campinas (UNICAMP), the University of Leicester, and Sao Paulo State University.