8SC7

Structure of EGFR in complex with MTX-531


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.186 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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Literature

A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

Whitehead, C.E.Ziemke, E.K.Frankowski-McGregor, C.L.Mumby, R.A.Chung, J.Li, J.Osher, N.Coker, O.Baladandayuthapani, V.Kopetz, S.Sebolt-Leopold, J.S.

(2024) Nat Cancer 5: 1250-1266

  • DOI: https://doi.org/10.1038/s43018-024-00781-6
  • Primary Citation of Related Structures:  
    8SC7, 8SC8, 8SC9

  • PubMed Abstract: 

    Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.


  • Organizational Affiliation

    Department of Radiology, University of Michigan, Ann Arbor, MI, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor330Homo sapiensMutation(s): 0 
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
Binding Affinity Annotations 
IDSourceBinding Affinity
D0D BindingDB:  8SC7 IC50: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.186 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 145.517α = 90
b = 145.517β = 90
c = 145.517γ = 90
Software Package:
Software NamePurpose
autoPROCdata processing
XDSdata reduction
Aimlessdata scaling
STARANISOdata scaling
REFMACrefinement
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted D0DClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-06-12
    Type: Initial release
  • Version 1.1: 2024-12-25
    Changes: Database references, Structure summary