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The protein at the KRAS gene structure is small in size and smooth in surface, like a shiny and smooth ball.
Pancreatic cancer is a highly malignant digestive system tumor and one of the most lethal cancer types among solid tumors
An important feature of pancreatic cancer is that about 95% of tumors carry KRAS gene mutations, which is one of the most dependent tumor types on KRAS gene mutations
A few days ago, the team of Professor Zhang Yonghui from the School of Pharmacy of Tsinghua University and Professor Guo Ruiting from the School of Life Sciences of Hubei University jointly developed a long-acting inhibitor TH-Z835 targeting KRAS-G12D, and revealed its unique dual-state targeting through crystallographic studies.
KRAS gene often 'untargetable'
Zhang Yonghui, the corresponding author of the paper, said: "When we develop drugs, we will carefully observe the structure of the target protein and look for compounds that can bind to two key sites
Amgen recently developed an inhibitor of KRAS-G12C, which can covalently bind to mutant cysteine 12 C12, and has been approved by the U.
However, the development of inhibitors of the oncogenic KRAS-G12D mutant common in pancreatic cancer has been poorly developed
However, none of these molecules efficiently targeted KRAS-G12D
Build an ingenious salt bridge
"We carefully studied the crystal structure of KRAS-G12D and found that the carboxylic acid group of the mutant aspartic acid at position 12 has a negative charge after deprotonation under physiological conditions, so we introduced a basic The positive and positively charged groups and the carboxylic acid of the mutant form a salt bridge
The protein of the KRAS gene structure has a nucleotide binding site that can bind guanosine diphosphate (GDP) or guanosine triphosphate (GTP) at very low concentrations
"In this study, the researchers found that the binding mode of G12D inhibitors is completely different from that of G12C inhibitors, and has a unique structural mechanism of action
"Therefore, the inhibitor can specifically bind to the KRAS-G12D mutant, inactivate the KRAS mutant protein, and no longer send growth or division instructions to cancer cells, so as to achieve the purpose of targeted inhibition of cancer