As the therapeutic significance of the proteolysis-targeting chimera (PROTAC®) continues to be realized, PROTAC® targeting proteins are crucially important as a novel therapeutic modality in drug discovery. Creative Biolabs has been a long-term expert in the field of PROTAC® development, and we can provide a variety of ligand design strategies for challenging PROTAC® development projects.
IKZF1 and IKZF3 (IKAROS family zinc finger 1 and 3) encode the member of the IKAROS family of zinc finger lymphoid transcription factors; these are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. IKZF1 and IKZF3 are the transcription factors that play an essential role in the regulation of B lymphocyte proliferation, differentiation, maturation to an effector state, and programmed cell death. Besides, IKZF1 and IKZF3 are shown to regulate the expression of hematopoiesis-specific genes and implement self-tolerance through the regulation of B-cell-receptor signaling. Diseases associated with IKZF1 and IKZF3 include immunodeficiency, leukemia, chronic lymphocytic and primary biliary cirrhosis, and severe cutaneous adverse reaction.
PROTAC® is a new modality that exploits the endogenous ubiquitin-proteasome system (UPS) to degrade a protein of interest for therapeutic benefits. IKZF1/3-targeting PROTAC® is a bifunctional molecule that recruits a target protein into proximity with an E3 ubiquitin ligase to trigger target ubiquitination and subsequent proteasomal degradation. Regulating protein function through IKZF1/3-targeted degradation has emerged as a new modality of discovery chemistry with attractive potential both as a tool for IKZF1/3 target validation and the development of novel therapeutics for IKZF1/3.
Fig.1 Family of IKZF transcription factors and IKZF1 isoforms. (Marke, 2018)
IKZF1 and IKZF3 are heterodimers formed by the various isoforms and modulate transcription regulator activity. The isoforms share a common C-terminal domain, which contains two zinc finger motifs that are required for hetero- or homo-dimerization, and interaction with other proteins. Additionally, the number of N-terminal zinc finger motifs and signal presence in nuclear localization result in members with DNA-binding properties.
With the continued success of the PROTAC® molecules, hit finding strategies to identify ligands for these targets are required for the development of PROTAC® targeting different targets. Depending on the specific structural characteristics of the IKZF1/3, Creative Biolabs can use a variety of strategies to generate high-quality ligands to fill the gap in the field. Based on different project requirements, there are multiple formats of IKZF1/3 ligand available that could be developed, including but not limited to a small molecule with structure-based computational methods for in silico screening, peptides and recombinant antibodies based on phage display. With the structural information, finding optimal ligands with high-throughput techniques facilitate successful PROTAC® design.
Using high-affinity optimized ligands for the protein of interest can recruit these E3 ubiquitin ligases to substrates. Creative Biolabs can also provide modification and engineering of existing ligands, which promotes these poorly selective or weak-affinity ligands to generate functional PROTAC®s as potential selective chemical probes or therapeutics tools. It provides a promising perspective for the PROTAC® approach with rapid and reversible efficacy.
Creative Biolabs has long-term devoted to the development of PROTAC®; our scientists are confident in offering the best and most suitable ligand design for our customers all over the world. If you are considering developing a novel PROTAC® against the target of interest, please do not hesitate to contact us for more details.
Reference
Our customer service representatives are available 24 hours a day, from Monday to Sunday. Contact Us