8S8C

Structure of Kras in complex with inhibitor MK-1084

This is a non-PDB format compatible entry.

Summary for 8S8C

• Entry DOI: 10.2210/pdb8s8c/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: nucleotide binding, gtpase, hydrolase, signal transduction, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20459.38

Authors

Day, P.J.,Cleasby, A. (deposition date: 2024-03-06, release date: 2024-07-10, Last modification date: 2024-10-23)

Primary citation

Ma, X.,Sloman, D.L.,Duggal, R.,Anderson, K.D.,Ballard, J.E.,Bharathan, I.,Brynczka, C.,Gathiaka, S.,Henderson, T.J.,Lyons, T.W.,Miller, R.,Munsell, E.V.,Orth, P.,Otte, R.D.,Palani, A.,Rankic, D.A.,Robinson, M.R.,Sather, A.C.,Solban, N.,Song, X.S.,Wen, X.,Xu, Z.,Yang, Y.,Yang, R.,Day, P.J.,Stoeck, A.,Bennett, D.J.,Han, Y.
Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS G12C Inhibitor.
J.Med.Chem., 67:11024-11052, 2024

PubMed Abstract: Oncogenic mutations in the gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

PubMed: 38924388
DOI: 10.1021/acs.jmedchem.4c00572

Experimental method

X-RAY DIFFRACTION (1.9 Å)