8SC8

Structure of PI3KG in complex with MTX-531


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.195 

Starting Model: experimental
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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
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform966Homo sapiensMutation(s): 0 
Gene Names: PIK3CG
EC: 2.7.1.153 (PDB Primary Data), 2.7.11.1 (PDB Primary Data), 2.7.1.137 (UniProt), 2.7.1.154 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for P48736 (Homo sapiens)
Explore P48736 
Go to UniProtKB:  P48736
PHAROS:  P48736
GTEx:  ENSG00000105851 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48736
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.195 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 143.934α = 90
b = 67.452β = 95.274
c = 106.983γ = 90
Software Package:
Software NamePurpose
autoPROCdata processing
XDSdata reduction
Aimlessdata scaling
STARANISOdata scaling
REFMACrefinement
REFMACphasing

Structure Validation

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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