Chemical acylation of an acquired serine suppresses oncogenic
2022年7月21日 · We show that K-Ras ligands that possess a β-lactone are potent electrophiles that bind to K-Ras (G12S) in the S-IIP and rapidly acylate the mutant serine residue, in much the same way that...
靶向KRAS-G12S的抑制剂设计与发现 - 搜狐
2022年8月1日 · 近日，来自美国加州大学旧金山分校的研究团队以Mirati公司开发的KRAS-G12C抑制剂adagrasib（MRTX849）为结构母核，引入能够共价靶向丝氨酸的β-内酯（β-lactone）结构，成功开发出了首个靶向KRAS-G12S突变体的选择性共价抑制剂。 在测定化合物活性之前，研究人员首先探询了KRAS蛋白的12位上甘氨酸到丝氨酸的突变是否足以使其产生致癌信号。 他们使用能够稳定表达KRAS-WT、KRAS-G12C和KRAS-G12S蛋白的Ba/F3细胞系和其特异性抗体进 …
Selective targeting of the oncogenic KRAS G12S mutant allele ... - PubMed
2020年4月6日 · Results: SpCas9 and dCas9-KRAB systems with a sgRNA targeting the mutant allele blocked the expression of the mutant KRAS gene, leading to an inhibition of cancer cell proliferation. Local adenoviral injections using SpCas9 and dCas9-KRAB systems suppressed tumor growth in vivo .
Codon-specific KRAS mutations predict survival benefit of
2023年3月2日 · Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12)...
文章就kras蛋白的结构和功能以及直接靶向kras g12c、kras g12d、kras g12r、kras G12S和泛KRAS抑制剂的研究现状、面临的挑战进行综述，旨在为KRAS抑制剂的发展提供有益参考。
Targeting cancer with small-molecule pan-KRAS degraders
2024年9月19日 · Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors.
Targeting KRAS in cancer - Nature Medicine
2024年4月18日 · Recent data demonstrate that BI-2865 can inhibit many of the common KRAS mutations seen in cancer, including G12D, G12V, G12C and p.Gly13Asp (G13D), as well as wild-type KRAS, which is...
KRAS in NSCLC: State of the Art and Future Perspectives
Within codon 12 mutations, the one resulting in the substitution of glycine with cysteine (KRAS G12C) represents the most prevalent KRAS alteration in NSCLC (40% of all KRAS mutant cases), followed by substitution of glycine with valine (KRAS G12V, 21%), and substitution of glycine with aspartic acid (KRAS G12D, 17%).
A Comparative Analysis of Individual RAS Mutations in Cancer …
When each KRAS mutant variant was analyzed independently, KRAS G12V and G12S were associated with 2- to 3-fold increase risk for long-term death compared to WT KRAS patients. In addition, patients carrying KRAS G12V, G12S, and G12C had a higher risk of death after recurrence compared to those harboring WT KRAS who recurred ( 73 ).
Innovative drugs promote precision cancer therapy
2023年12月6日 · G12Si series compounds have been demonstrated to covalently modify the KRAS protein to a certain extent, reduce the content of KRAS-GTP, and significantly inhibit the level of phosphorylated ERK in cells. KRAS-G12S inhibitors provide a new option for the development of other serine-targeted covalent inhibitors.