Based on extensive experience, Creative Biolabs has built an advanced Protein Degraders platform that can be used to design suitable ligands for c-Abl-targeting Protein Degraders. Protein kinases are an intensively focused drug target family thanks to their engagement in different indications, including cancer, inflammation, metabolic diseases, and immune disorders. Here, we are pleased to provide custom ligand design services for c-Abl kinases by generating a hybrid molecule or peptide to specifically knockdown this target.
The Abl family of cytoplasmic tyrosine kinases contains two members, Abl and Arg, encoded by ABL1 and ABL2 genes in humans, and has significant roles in many biological processes. c-Abl is a non-receptor tyrosine kinase that comprises 3 structural domains in the N-terminal region (SH2, SH3, and catalytic kinase domains). This kinase is characterized by a long C-terminal tail, which is crucial for its functions. The tail region has 3 proline-rich motifs, allowing interactions with SH3 containing proteins. This region also contains 3 nuclear localization signals (NLSs) and a single nuclear export signal (NES) motif, a putative DNA-binding domain (DBD) with 3 high mobility group-like domains and an actin-binding domain. There are two c-Abl isoforms originated from alternative splicing activities, including c-Abl 1a and 1b. Despite both of them share an N-terminal cap region, the cap of c-Abl 1b is about 20 amino acids longer than that of c-Abl 1a.
Fig.1 Full view of the assembled c-Abl structure. (Hong, 2014)
c-Abl and its variants are implicated in tumorigenesis and a variety of important cellular processes. The effects of c-Abl are mediated by its tyrosine kinase domain and many different protein-DNA and protein-protein interactions. It is believed to take a part in cell cycle regulation, oxidation and ionization, stress responses to DNA damage, and signal transduction caused by external stimulus. Evidence demonstrates that c-Abl activation might result in the inhibition of mammary tumorigenesis and cancer cell invasion and metastasis. As well, c-Abl activation is likely to act in the process of myelopoiesis.
Protein Degraders are bifunctional molecules that employ the ubiquitin-proteasome system to accomplish the degradation of a disease-related protein. The ubiquitination and autophagy routes are major pathways for the degradation of target proteins and the maintenance of homeostasis. At Creative Biolabs, we focus on the principle and mechanisms of this emerging technology and summarize new progress and characteristics of Protein Degraders, particularly those with high selectivity.
Fig.2 A schematic diagram of the small molecule-based Protein Degraders. (Zou, 2019)
Today, our technical teams have developed small-molecule Protein Degraders with good pharmaceutical properties to help clients identify ideal ligands for c-Abl and other protein kinases. There’re multiple strategies can be used to produce high-quality ligands based on the structural information of c-Abl and other required targets. We highlight the advantages of small-molecule Protein Degraders over small molecule inhibitors, which are the currently predominant type of targeted therapies towards associated proteins. Meanwhile, our experts also introduce other formats of c-Abl ligand products, including peptides and recombinant antibodies, exhibiting the recent advancement of Protein Degraders technology.
Protein Degraders are well-documented as a unique modality in drug discovery and development. They represent remarkable biological responses in different targets, including an excellent selectivity over protein kinase family members and even an outstanding efficacy covering weak or unspecific binders. As a first-class supplier in molecular discovery, Creative Biolabs pays attention to the latest characters of Protein Degraders technology, such as showing enhanced target selectivity, causing a potent inhibition of downstream signals, and leading to a fast and sustained degradation. We are committed to providing optimized ligand design services for c-Abl kinase and devoted to the development of Protein Degraders targeting other desired targets. For more details, please don't hesitate to contact us.
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