However due to the extraordinarily high affinity of GTP/GDP for this site, it is unlikely that drug-like small molecule inhibitors could compete with GTP/GDP binding. Other than where GTP/GDP binds, there are no obvious high affinity binding sites for small molecules.[38] One fairly frequent driver mutation is KRASG12C which is adjacent a shallow binding site. This has allowed the development of electrophilic KRAS inhibitors that can form irreversible covalent bonds with nucleophilic sulfur atom of Cys-12 and hence selectively target KRASG12C and leave wild-type KRAS untouched.[39] Two KRASG12C mutant covalent inhibitors have reached clinical testing: AMG 510 (Amgen)[40] and MRTX-849 (Mirati Therapeutics)[41] while ARS-3248 (Wellspring Biosciences/Janssen) has received an investigational new drug (IND) approval to start clinical trials.[42] An antisense oligonucleotide (ASO), AZD4785 (AstraZeneca/Ionis Therapeutics) targeting KRAS has completed a phase I study[43] but was discontinued from further development because of insufficient knockdown of the target.[44]