Developing and Characterization of Chemically Modified RNA Aptamers for Targeting Wild Type and Mutated c-KIT Receptor Tyrosine Kinases.
Ala'a S ShraimAbdelrahim HunaitiAbdalla AwidiWalhan AlshaerNidaa A AbabnehBashaer Abu-IrmailehFadwa OdehSaid IsmailPublished in: Journal of medicinal chemistry (2019)
The c-KIT receptor represents an attractive target for cancer therapy. Aptamers are emerging as a new promising class of nucleic acid therapeutics. In this study, a conventional SELEX approach was applied against the kinase domain of a group of c-KIT proteins (c-KITWT, c-KITD816V, and c-KITD816H) to select aptamers from a random RNA pool that can bind to the kinase domain of each target with high affinity and can selectively interfere with their kinase activities. Interestingly, our data indicated that one candidate aptamer, called V15, can specifically inhibit the in vitro kinase activity of mutant c-KITD816V with an IC50 value that is 9-fold more potent than the sunitinib drug tested under the same conditions. Another aptamer, named as H5/V36, showed the potential to distinguish between the c-KIT kinases by modulating the phosphorylation activity of each in a distinct mechanism of action and in a different potency.
Keyphrases
- nucleic acid
- wild type
- protein kinase
- cancer therapy
- tyrosine kinase
- sensitive detection
- small molecule
- signaling pathway
- drug delivery
- electronic health record
- big data
- deep learning
- artificial intelligence
- magnetic nanoparticles
- renal cell carcinoma
- anti inflammatory
- binding protein
- drug induced
- label free
- human health