6EPN

Ras guanine exchange factor SOS1 (Rem-cdc25) in complex with KRAS(G12C) and fragment screening hit F2

Summary for 6EPN

• Entry DOI: 10.2210/pdb6epn/pdb
• Related: 6EPL 6EPM 6EPO 6EPP
• Descriptor: GTPase KRas, Son of sevenless homolog 1, GLYCEROL, ... (6 entities in total)
• Functional Keywords: guanine nucleotide exchange factor, gef, fragment screen, gtpase, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 76851.59

Authors

Hillig, R.C.,Moosmayer, D.,Hilpmann, A.,Bader, B.,Schroeder, J.,Wortmann, L.,Sautier, B.,Kahmann, J.,Wegener, D.,Briem, H.,Petersen, K.,Badock, V. (deposition date: 2017-10-12, release date: 2019-02-06, Last modification date: 2024-01-17)

Primary citation

Hillig, R.C.,Sautier, B.,Schroeder, J.,Moosmayer, D.,Hilpmann, A.,Stegmann, C.M.,Werbeck, N.D.,Briem, H.,Boemer, U.,Weiske, J.,Badock, V.,Mastouri, J.,Petersen, K.,Siemeister, G.,Kahmann, J.D.,Wegener, D.,Bohnke, N.,Eis, K.,Graham, K.,Wortmann, L.,von Nussbaum, F.,Bader, B.
Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.
Proc. Natl. Acad. Sci. U.S.A., 116:2551-2560, 2019

PubMed Abstract: Since the late 1980s, mutations in the 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 molecular 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-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS-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 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC of 21 nM and is a valuable chemical probe for future investigations.

PubMed: 30683722
DOI: 10.1073/pnas.1812963116

Experimental method

X-RAY DIFFRACTION (2.5 Å)