5C8K

EGFR kinase domain mutant "TMLR" with compound 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

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

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

(2015) J Med Chem 58: 8877-8895

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01412
  • Primary Citation of Related Structures:  
    5C8K, 5C8M, 5C8N, 5CAL, 5CAN, 5CAO, 5CAP, 5CAQ, 5CAS, 5CAU, 5CAV

  • PubMed 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.


  • Organizational Affiliation

    Argenta, Early Discovery Charles River , 7/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor331Homo sapiensMutation(s): 5 
Gene Names: EGFRERBBERBB1HER1
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens)
Explore P00533 
Go to UniProtKB:  P00533
PHAROS:  P00533
GTEx:  ENSG00000146648 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00533
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4YV
Query on 4YV

Download Ideal Coordinates CCD File 
B [auth A]1-cyclopentyl-N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-1H-imidazo[4,5-c]pyridin-6-amine
C21 H27 N7 O
HVRZVMCNHMWTOQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4YV BindingDB:  5C8K Ki: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 146.454α = 90
b = 146.454β = 90
c = 146.454γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-28
    Type: Initial release
  • Version 1.1: 2015-11-25
    Changes: Database references
  • Version 1.2: 2015-12-02
    Changes: Database references
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Derived calculations