KRAS, the most frequently mutated oncogene, plays a predominant role in driving initiation and progression of cancers. Decades of effort to target KRAS using small molecules has been unsuccessful, causing KRAS to be considered an “undruggable” cancer target^[1]. However, this view began to change recently, as drug discovery techniques have developed several KRAS allosteric inhibitors. in May 2021, Amgen's KRAS G12C inhibitor, commonly known as Sotorasib, was approved by the US FDA and was the first targeted drug for the treatment of cancer with KRAS gene mutation in the world. At present, a number of small molecule drugs targeting KRAS G12C are in clinical stages and the fastest progress is adagrasib (MATX849) of Mirati therapeutics, which is expected to become the second KRAS G12C targeted drug in the world. And on December 10, 2021, Journal of Medicinal Chemistry reported the discovery and characterization of the first Noncovalent, Potent, and Selective KRAS G12D Inhibitor MARTX1133^[2-9].

A series of building blocks will be used as molecular fragments
in the design of KRAS inhibitors.