The role and efficacy of PROTAC in FLT3-mutated AML treatment

Abstract

Small molecule Proteolysis Targeting Chimera (PROTAC) is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML). By activating the ubiquitination system, PROTAC can generate protein and kinase degradation upon FLT3 to perform outcomes of antiproliferative activities. The focus of this study revolves around the investigation of the efficacy of VHL and CRBN-based PROTAC on FLT3 degradation compared to conventional immunotherapy agents such as quizartinib. By assessing the performances of PROTAC on MOLM-14 and MV4-11 cells with other therapies, comparing both adverse effects and benefits could demonstrate crucial approaches to applying PROTAC for AML treatments. The VHL-recruiting PROTAC based on the modification of quizartinib has shown promising effects where FLT3 within MV4-11 injected athymic mice had experienced around a 60% of decrease. The CRBN-based degrader TL12-186, on the other hand, had also demonstrated antiproliferative outcomes where 14 out of 7559 proteins of the MOLM-14 cell have been successfully degraded, showing a more than 25% decrease. Even though there seem to be some improvements in the VHL-recruiting PROTAC compared to traditional immunotherapy agents like quizartinib, CRBN-mediated PROTAC has shown a relatively less significant result. Critiquing in a variety of aspects, quizartinib has demonstrated better performance in cell permeability, low nanomolecular concentration, and degradation. The significance of this study provides an overview of existing PROTAC technology that shows effects on the treatment of FLT3-mutated AML. Further studies may be conducted on the foundation of this study to demonstrate the enhancements of each modified PROTAC compared to existing therapies.