Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA); Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA); Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA).
Angew Chem Int Ed Engl. 2014 Jan 3;53(1):199-204. doi: 10.1002/anie.201307387. Epub 2013 Nov 20.
We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
我们报告了 GDP 类似物 SML-8-73-1 和前药衍生物 SML-10-70-1 的合成，它们是相对于野生型 Ras 对 K-Ras G12C 突变体具有选择性和直接作用的共价抑制剂。生化和生物物理测量表明，SML-8-73-1 对 K-Ras 的修饰使该蛋白处于无活性状态。这些首个类别的共价 K-Ras 抑制剂表明，不可逆地靶向 K-Ras 鸟嘌呤核苷酸结合位点可能是抑制 Ras 信号传导的一种可行的治疗策略。
