AMG 510: the kryptonite of mutant KRASG12C

Over three decades of cancer therapy research have been dedicated to investigating the most frequently mutated oncogene: KRAS. Approximately one million cancer deaths per year worldwide are traced to mutations in KRAS, which promote tumour formation and survival. Countless failed anti-KRAS therapies have deemed KRAS “undruggable”, as traditional medicinal chemistry seemed ill-equipped to design drugs against proteins, such as KRAS, with no obvious binding sites or “pockets”. Recently, the clinical development of a covalently binding small molecule known as AMG 510 has suggested that it may be the most promising anti-KRAS therapy. KRAS resides within the RAS family of GTPase proteins described as on/off switches for cell growth and proliferation. The desire to specifically target mutant KRASG12C stems from its presence in some of the deadliest cancers, such as colorectal, pancreatic, and lung adenocarcinomas. The substitution of guanine with nucleophilic cysteine disrupts the GTPase activity of KRAS so that it is persistently active, forcing cells into a hyperproliferative state that increases susceptibility to mutation.