Long-Awaited Small-Molecule Drug Candidate for Drugging the Next Undruggable KRAS^G12D Mutant in Cancer Therapy

Abstract

Disease Area. Cancer Biological Target. KRAS G12D mutant Summary. RAS (the rat sarcoma viral oncogene homologue) encodes a membrane-bound protein; it was initially described in the 1960s by Harvey and Kirsten as a retroviral oncogene involved in cells. However, it was in 1982 that the transforming properties of RAS were reported in human bladder cancer cell lines, which is considered the most frequently mutated oncogene in humans. Notably, the KRAS (Kirsten rat sarcoma viral oncogene) isoform represents 75% of RAS mutant cancers. RAS (KRAS, NRAS, and HRAS) proteins regulate key cellular pathway transmitting signals received from cellular membrane receptors to essential downstream molecules such as Raf, MEK, ERK, and PI3K. RAS protein is composed of three major domains: the Gdomain, which is highly conserved between RAS isoforms and contains switch-I and switch-II loops that are responsible for GTP-GDP exchange; the C-terminal domain, also known as

Discovery of potent and noncovalent KRASG12D inhibitors: Structure-based virtual screening and biological evaluation

“…Recent studies have revealed that mutated KRAS expression is associated with reduced anticancer activity of gemcitabine and paclitaxel, the drugs currently used in the clinical treatment of pancreatic cancer, and new therapeutic strategies of targeting KRAS should inhibit tumor cell growth and combat drug resistance ( Kimmelman, 2015 ; Grasso et al, 2017 ). The majority of cancer-associated hotspot mutations occur at codons G12, G13, and Q61, wherein G12 represents the most common mutation site ( Kargbo, 2022 ). Among dominant mutations at G12, G12D has the highest mutation frequency (35.4%), followed by G12V (23.5%), G12R (8.7%) and G12C (4.3%), which has aroused the interest of many drug researchers in developing new cancer treatment methods targeting KRAS G12D mutant ( Salem et al, 2021 ).…”