6TAN

X-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQUINOLINONE INHIBITOR (COMPOUND 17)

Summary for 6TAN

• Entry DOI: 10.2210/pdb6tan/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kras, inhibitor, covalent binding, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20201.69

Authors

Hillig, R.C.,Eis, K.,Badock, V. (deposition date: 2019-10-30, release date: 2020-04-08, Last modification date: 2024-11-06)

Primary citation

Mortier, J.,Friberg, A.,Badock, V.,Moosmayer, D.,Schroeder, J.,Steigemann, P.,Siegel, F.,Gradl, S.,Bauser, M.,Hillig, R.C.,Briem, H.,Eis, K.,Bader, B.,Nguyen, D.,Christ, C.D.
Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.
Chemmedchem, 15:827-832, 2020

PubMed Abstract: Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRAS has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRAS covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRAS . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRAS complex highlighted an unprecedented binding mode.

PubMed: 32237114
DOI: 10.1002/cmdc.201900727

Experimental method

X-RAY DIFFRACTION (1.16 Å)