PDBsum entry 6pgo

Signaling protein/inhibitor

PDB id: 6pgo

Contents

Protein chains

160 a.a.

152 a.a.

Ligands

GDP ×2

OJ1 ×2

Metals

_MG ×2

Waters ×163

PDB id:

6pgo

Name:

Signaling protein/inhibitor

Title:

Crystal structure of human kras g12c covalently bound to a phthalazine inhibitor

Structure:

Gtpase kras. Chain: a, b. Synonym: k-ras 2,ki-ras,c-k-ras,c-ki-ras. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Variant: var_006839 g12c. Gene: kras, kras2, rask2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.60Å R-factor: 0.218 R-free: 0.231

Authors:

C.Mohr

Key ref:

B.A.Lanman et al. (2020). Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem, 63, 52-65. PubMed id: 31820981 DOI: 10.1021/acs.jmedchem.9b01180

Date:

24-Jun-19 Release date: 25-Dec-19

Protein chain

P01116  (RASK_HUMAN) -  GTPase KRas from Homo sapiens

Seq: 189 a.a.

Struc: 160 a.a.*

Protein chain

P01116  (RASK_HUMAN) -  GTPase KRas from Homo sapiens

Seq: 189 a.a.

Struc: 152 a.a.*

* PDB and UniProt seqs differ at 19 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: 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.9b01180

J Med Chem 63:52-65 (2020)

PubMed id: 31820981

Discovery of a Covalent Inhibitor of KRAS^G12C (AMG 510) for the Treatment of Solid Tumors.

B.A.Lanman, J.R.Allen, J.G.Allen, A.K.Amegadzie, K.S.Ashton, S.K.Booker, J.J.Chen, N.Chen, M.J.Frohn, G.Goodman, D.J.Kopecky, L.Liu, P.Lopez, J.D.Low, V.Ma, A.E.Minatti, T.T.Nguyen, N.Nishimura, A.J.Pickrell, A.B.Reed, Y.Shin, A.C.Siegmund, N.A.Tamayo, C.M.Tegley, M.C.Walton, H.L.Wang, R.P.Wurz, M.Xue, K.C.Yang, P.Achanta, M.D.Bartberger, J.Canon, L.S.Hollis, J.D.McCarter, C.Mohr, K.Rex, A.Y.Saiki, T.San Miguel, L.P.Volak, K.H.Wang, D.A.Whittington, S.G.Zech, J.R.Lipford, V.J.Cee.

ABSTRACT

KRAS^G12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS^G12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS^G12C inhibitor currently in phase I clinical trials (NCT03600883).