8AQ5

KRAS G12C IN COMPLEX WITH GDP AND COMPOUND 16

Summary for 8AQ5

• Entry DOI: 10.2210/pdb8aq5/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, 1-[6-[4-(5-chloranyl-6-methyl-1~{H}-indazol-4-yl)-5-methyl-3-phenyl-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]propan-1-one, ... (5 entities in total)
• Functional Keywords: k-ras g12c, gtpase, gdp bound, cysteine mutation, covalent binding, signaling protein, small g-protein, switch2 pocket, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20294.29

Authors

Ostermann, N. (deposition date: 2022-08-11, release date: 2022-12-07, Last modification date: 2024-10-09)

Primary citation

Lorthiois, E.,Gerspacher, M.,Beyer, K.S.,Vaupel, A.,Leblanc, C.,Stringer, R.,Weiss, A.,Wilcken, R.,Guthy, D.A.,Lingel, A.,Bomio-Confaglia, C.,Machauer, R.,Rigollier, P.,Ottl, J.,Arz, D.,Bernet, P.,Desjonqueres, G.,Dussauge, S.,Kazic-Legueux, M.,Lozac'h, M.A.,Mura, C.,Sorge, M.,Todorov, M.,Warin, N.,Zink, F.,Voshol, H.,Zecri, F.J.,Sedrani, R.C.,Ostermann, N.,Brachmann, S.M.,Cotesta, S.
JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRAS G12C for the Treatment of Solid Tumors.
J.Med.Chem., 65:16173-16203, 2022

PubMed Abstract: Rapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRAS inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRAS inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRAS C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

PubMed: 36399068
DOI: 10.1021/acs.jmedchem.2c01438

Experimental method

X-RAY DIFFRACTION (1.8 Å)