PDBsum entry 5cau

Transferase/transferase inhibitor

PDB id: 5cau

Contents

Protein chain

297 a.a.

Ligands

SO4

4ZR

Waters ×101

PDB id:

5cau

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase domain mutant "tmlr" with compound 41b

Structure:

Epidermal growth factor receptor. Chain: a. 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:

2.25Å R-factor: 0.188 R-free: 0.211

Authors:

C.Eigenbrot,C.Yu

Key ref:

R.Heald et al. (2015). Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study. J Med Chem, 58, 8877-8895. PubMed id: 26455919 DOI: 10.1021/acs.jmedchem.5b01412

Date:

29-Jun-15 Release date: 28-Oct-15

Protein chain

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

Seq: 1210 a.a.

Struc: 297 a.a.*

* PDB and UniProt seqs differ at 2 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.5b01412

J Med Chem 58:8877-8895 (2015)

PubMed id: 26455919

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.

R.Heald, K.K.Bowman, M.C.Bryan, D.Burdick, B.Chan, E.Chan, Y.Chen, S.Clausen, B.Dominguez-Fernandez, C.Eigenbrot, R.Elliott, E.J.Hanan, P.Jackson, J.Knight, H.La, M.Lainchbury, S.Malek, S.Mann, M.Merchant, K.Mortara, H.Purkey, G.Schaefer, S.Schmidt, E.Seward, S.Sideris, L.Shao, S.Wang, K.Yeap, I.Yen, C.Yu, T.P.Heffron.

ABSTRACT

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.