PDBsum entry 5hg8

Transferase/transferase inhibitor

PDB id: 5hg8

Contents

Protein chain

300 a.a.

Ligands

634

SO4 ×2

GOL

Waters ×209

PDB id:

5hg8

Name:

Transferase/transferase inhibitor

Title:

Egfr (l858r, t790m, v948r) in complex with n-[3-({2-[(1-methyl-1h- pyrazol-4-yl)amino]-7h-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)phenyl]prop- 2-enamide

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 frugiperda. Expression_system_taxid: 7108

Resolution:

1.42Å R-factor: 0.208 R-free: 0.213

Authors:

K.S.Gajiwala

Key ref:

H.Cheng et al. (2016). Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants. J Med Chem, 59, 2005-2024. PubMed id: 26756222 DOI: 10.1021/acs.jmedchem.5b01633

Date:

08-Jan-16 Release date: 03-Feb-16

Protein chain

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

Seq: 1210 a.a.

Struc: 300 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.5b01633

J Med Chem 59:2005-2024 (2016)

PubMed id: 26756222

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.

H.Cheng, S.K.Nair, B.W.Murray, C.Almaden, S.Bailey, S.Baxi, D.Behenna, S.Cho-Schultz, D.Dalvie, D.M.Dinh, M.P.Edwards, J.L.Feng, R.A.Ferre, K.S.Gajiwala, M.D.Hemkens, A.Jackson-Fisher, M.Jalaie, T.O.Johnson, R.S.Kania, S.Kephart, J.Lafontaine, B.Lunney, K.K.Liu, Z.Liu, J.Matthews, A.Nagata, S.Niessen, M.A.Ornelas, S.T.Orr, M.Pairish, S.Planken, S.Ren, D.Richter, K.Ryan, N.Sach, H.Shen, T.Smeal, J.Solowiej, S.Sutton, K.Tran, E.Tseng, W.Vernier, M.Walls, S.Wang, S.L.Weinrich, S.Xin, H.Xu, M.J.Yin, M.Zientek, R.Zhou, J.C.Kath.

ABSTRACT

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.