Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy.

Abstract

Introduction: Transcription factors (TFs) are master regulators of cellular function and orchestrate diverse signaling pathways and processes. Acting as convergence points of signaling pathways, they integrate extracellular stimuli with intracellular responses to regulate cell functions. Dysregulation of TFs drives tumorigenesis including proliferation, drug resistance, and immune evasion of multiple myeloma (MM), the second most-common hematologic malignancy.

Areas covered: The discovery that IMiDs are molecular glue degraders, which reprogram the E3-ligase cereblon (CRBN) to ubiquitinate and degrade IKZF1 and IKZF3, two otherwise un-druggable crucial TFs in MM, gave rise to the widespread interest in proximity-induced protein-degradation as an exciting novel therapeutic strategy. This review summarizes our up-to-date knowledge on the pre/clinical development of IMiD-related, more potent CRBN E3-Ligase Modulatory Drugs (CELMoDs), directed PROteolysis TArgeting Chimeras (PROTACs) and degronomids as well as on promising future avenues in the field of targeted protein-degradation (TPD).

Expert opinion: TPD is an emerging field to treat cancer, including MM. CELMoDs are already reshaping the treatment landscape of MM. Preclinical data on PROTACs are promising. Nevertheless, a deeper understanding of TF biology as well as further advancements in screening methodologies and chemoproteomics are crucial to further spur the transformative potential of targeted TF degradation in MM.