PDBsum entry 6t5u

Signaling protein

PDB id: 6t5u

Contents

Protein chains

168 a.a.

Ligands

GDP ×2

MKW ×2

Metals

_MG ×2

Waters ×168

PDB id:

6t5u

Name:

Signaling protein

Title:

Krasg12c ligand complex

Structure:

V-ki-ras2 kirsten rat sarcoma viral oncogene homolog, isoform cra_b. Chain: a, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kras, hcg_14731. Expressed in: escherichia phage ecszw-2. Expression_system_taxid: 2419741

Resolution:

1.72Å R-factor: 0.240 R-free: 0.291

Authors:

C.Phillips

Key ref:

J.G.Kettle et al. (2020). Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRAS^G12C. J Med Chem, 63, 4468-4483. PubMed id: 32023060 DOI: 10.1021/acs.jmedchem.9b01720

Date:

17-Oct-19 Release date: 19-Feb-20

Protein chains

A0A1S2ZE25  (A0A1S2ZE25_ERIEU) -  small monomeric GTPase from Erinaceus europaeus

Seq: 188 a.a.

Struc: 168 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GDP) corresponds exactly) + phosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.9b01720

J Med Chem 63:4468-4483 (2020)

PubMed id: 32023060

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRAS^G12C.

J.G.Kettle, S.K.Bagal, S.Bickerton, M.S.Bodnarchuk, J.Breed, R.J.Carbajo, D.J.Cassar, A.Chakraborty, S.Cosulich, I.Cumming, M.Davies, A.Eatherton, L.Evans, L.Feron, S.Fillery, E.S.Gleave, F.W.Goldberg, S.Harlfinger, L.Hanson, M.Howard, R.Howells, A.Jackson, P.Kemmitt, J.K.Kingston, S.Lamont, H.J.Lewis, S.Li, L.Liu, D.Ogg, C.Phillips, R.Polanski, G.Robb, D.Robinson, S.Ross, J.M.Smith, M.Tonge, R.Whiteley, J.Yang, L.Zhang, X.Zhao.

ABSTRACT

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS^G12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRAS^G12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.