Hillig, Roman C. published the artcileDiscovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction, Computed Properties of 1150271-51-4, the publication is Proceedings of the National Academy of Sciences of the United States of America (2019), 116(7), 2551-2560, database is CAplus and MEDLINE.
Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this mol. switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-mol. inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophys. techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23(I, BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chem. probe for future investigations.
Proceedings of the National Academy of Sciences of the United States of America published new progress about 1150271-51-4. 1150271-51-4 belongs to ethers-buliding-blocks, auxiliary class Boronic acid and ester,Amine,Benzene,Ether,Boronate Esters,Boronic Acids,Boronic acid and ester,, name is 2-Methoxy-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)ethanamine, and the molecular formula is C16H26BNO3, Computed Properties of 1150271-51-4.
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