9E9I
Crystal Structure of human KRAS G12C covalently bound to nopinone-derived naphthol compound 21
This is a non-PDB format compatible entry.
Summary for 9E9I
| Entry DOI | 10.2210/pdb9e9i/pdb |
| Related | 9E9H |
| Descriptor | Isoform 2B of GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total) |
| Functional Keywords | inhibitor, gtpase, signaling protein, oncoprotein-inhibitor complex, oncoprotein/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 22277.25 |
| Authors | Mohr, C. (deposition date: 2024-11-08, release date: 2025-02-26, Last modification date: 2025-03-05) |
| Primary citation | Huang, D.,Manoni, F.,Sun, Z.,Liu, R.,Allen, J.R.,Banerjee, A.,Cee, V.J.,Eshon, J.,Frohn, M.J.,Kaller, M.R.,Lee, H.,Li, C.,Li, X.,Lopez, P.,Ma, V.,Medina, J.M.,Mohr, C.,Mukhina, O.A.,Pickrell, A.J.,Stellwagen, J.,Wu, W.,Zhang, W.,Zhu, K.,Dahal, U.P.,Hu, L.A.,Leavitt, M.,Li, W.,Li, Y.,Ma, Y.,Rex, K.,Saiki, A.Y.,Wang, P.,Sun, Y.,Dai, D.,Tamayo, N.A.,Lanman, B.A. Identification of Structurally Novel KRAS G12C Inhibitors through Covalent DNA-Encoded Library Screening. J.Med.Chem., 68:4801-4817, 2025 Cited by PubMed Abstract: Covalent inhibition of the KRAS oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRAS. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRAS with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects. PubMed: 39930787DOI: 10.1021/acs.jmedchem.4c03071 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.18 Å) |
Structure validation
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