7UKR

Crystal Structure of SOS1 with MRTX0902, a Potent and Selective Inhibitor of the SOS1:KRAS Protein-Protein Interaction

Summary for 7UKR

• Entry DOI: 10.2210/pdb7ukr/pdb
• Descriptor: Son of sevenless homolog 1, 2-methyl-3-[(1R)-1-{[4-methyl-7-(morpholin-4-yl)pyrido[3,4-d]pyridazin-1-yl]amino}ethyl]benzonitrile (3 entities in total)
• Functional Keywords: sos1, kras, ras, protein-protein interaction, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 114983.50

Authors

Gunn, R.J.,Lawson, J.D.,Ketcham, J.M.,Marx, M.A. (deposition date: 2022-04-01, release date: 2022-07-27, Last modification date: 2023-10-18)

Primary citation

Ketcham, J.M.,Haling, J.,Khare, S.,Bowcut, V.,Briere, D.M.,Burns, A.C.,Gunn, R.J.,Ivetac, A.,Kuehler, J.,Kulyk, S.,Laguer, J.,Lawson, J.D.,Moya, K.,Nguyen, N.,Rahbaek, L.,Saechao, B.,Smith, C.R.,Sudhakar, N.,Thomas, N.C.,Vegar, L.,Vanderpool, D.,Wang, X.,Yan, L.,Olson, P.,Christensen, J.G.,Marx, M.A.
Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.
J.Med.Chem., 65:9678-9690, 2022

PubMed Abstract: SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRAS protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRAS, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRAS. In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRAS PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.

PubMed: 35833726
DOI: 10.1021/acs.jmedchem.2c00741

Experimental method

X-RAY DIFFRACTION (2.5 Å)