PDBsum entry 5ug9

Transferase/transferase inhibitor

PDB id: 5ug9

Contents

Protein chain

280 a.a.

Ligands

8AM

SO4 ×2

GOL ×3

EDO

Waters ×302

PDB id:

5ug9

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of the egfr kinase domain (l858r, t790m, v948r) in complex with a covalent inhibitor n-[(3r,4r)-4-fluoro-1-{6-[(3- methoxy-1-methyl-1h-pyrazol-4-yl)amino]-9-(propan-2-yl)-9h-purin-2- yl}pyrrolidin-3-yl]propanamide

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: unp residues 695-1022. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera aff. Frugiperda 2 rz-2014. Expression_system_taxid: 1491790

Resolution:

1.33Å R-factor: 0.195 R-free: 0.205

Authors:

K.S.Gajiwala,R.A.Ferre

Key ref:

S.Planken et al. (2017). Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR. J Med Chem, 60, 3002-3019. PubMed id: 28287730 DOI: 10.1021/acs.jmedchem.6b01894

Date:

07-Jan-17 Release date: 22-Mar-17

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 280 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

Added reference

DOI no: 10.1021/acs.jmedchem.6b01894

J Med Chem 60:3002-3019 (2017)

PubMed id: 28287730

Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.

S.Planken, D.C.Behenna, S.K.Nair, T.O.Johnson, A.Nagata, C.Almaden, S.Bailey, T.E.Ballard, L.Bernier, H.Cheng, S.Cho-Schultz, D.Dalvie, J.G.Deal, D.M.Dinh, M.P.Edwards, R.A.Ferre, K.S.Gajiwala, M.Hemkens, R.S.Kania, J.C.Kath, J.Matthews, B.W.Murray, S.Niessen, S.T.Orr, M.Pairish, N.W.Sach, H.Shen, M.Shi, J.Solowiej, K.Tran, E.Tseng, P.Vicini, Y.Wang, S.L.Weinrich, R.Zhou, M.Zientek, L.Liu, Y.Luo, S.Xin, C.Zhang, J.Lafontaine.

ABSTRACT

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.