Li, Ling published the artcileDiscovery of Thieno[2,3-d]pyrimidine-based KRAS G12D inhibitors as potential anticancer agents via combinatorial virtual screening, Computed Properties of 145349-62-8, the publication is European Journal of Medicinal Chemistry (2022), 114243, database is CAplus and MEDLINE.
A series of novel thieno[2,3-d]pyrimidine analogs were designed and synthesized as KRAS G12D inhibitors via combinatorial virtual screening approach. Most compounds exhibited potent antiproliferative activity on KRAS G12D mutated cancer cell lines (Panc1, SW1990 and CT26) with IC50 values in the low micromolar range. Among them, I (R = 2-OCH3-5-CF3) showed the highest antiproliferative activity with an average IC50 of 2.1μM against three KRAS G12D-mutated cells (Panc1, SW1990 and CT26). CompoundI (R = 2-OCH3-5-CF3) decreased the active form of KRAS (KRAS-GTP) in KRAS G12D mutated cancer cell lines (CT26 and SW1990) but not in KRAS G13D mutated cancer cells (HCT116). Moreover, I (R = 2-OCH3-5-CF3) down-regulated the phosphorylated Raf and Erk in CT26 and SW1990 cancer cell lines but not in HeLa cells (KRAS WT). The binding affinity of I (R = 2-OCH3-5-CF3) was further confirmed by the isothermal titration calorimetry (ITC) assay in which I (R = 2-OCH3-5-CF3) exhibited a KD of 33 nM for binding to KRAS G12D protein. In addition, I (R = 2-OCH3-5-CF3) (40 mg/kg or 60 mg/kg) exhibited significant antitumor efficacy in a CT26 tumor model with a tumor growth inhibition (TGI) of 42% or 53% without causing apparent toxicity. Taken together the above results suggest that I (R = 2-OCH3-5-CF3) is a promising KRAS G12D inhibitor deserving further investigation.
European Journal of Medicinal Chemistry published new progress about 145349-62-8. 145349-62-8 belongs to chlorides-buliding-blocks, auxiliary class Chloride,Boronic acid and ester,Benzene,Boronic Acids, name is 2-Chloro-4-methylphenylboronic acid, and the molecular formula is C7H8BClO2, Computed Properties of 145349-62-8.
Referemce:
https://en.wikipedia.org/wiki/Chloride,
Chlorides – an overview | ScienceDirect Topics