9AY7

Crystal structure of CRAF/MEK1 complex with NST-628 and inactive RAF


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Ryan, M.B.Quade, B.Schenk, N.Fang, Z.Zingg, M.Cohen, S.E.Swalm, B.M.Li, C.Ozen, A.Ye, C.Ritorto, M.S.Huang, X.Dar, A.C.Han, Y.Hoeflich, K.P.Hale, M.Hagel, M.

(2024) Cancer Discov 14: 1190-1205

  • DOI: https://doi.org/10.1158/2159-8290.CD-24-0139
  • Primary Citation of Related Structures:  
    9AXA, 9AXC, 9AXH, 9AXM, 9AXX, 9AXY, 9AY7, 9AYA

  • PubMed Abstract: 

    Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.


  • Organizational Affiliation

    Nested Therapeutics, Cambridge, MA, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RAF proto-oncogene serine/threonine-protein kinase280Homo sapiensMutation(s): 2 
Gene Names: RAF1RAF
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04049 (Homo sapiens)
Explore P04049 
Go to UniProtKB:  P04049
PHAROS:  P04049
GTEx:  ENSG00000132155 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04049
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity mitogen-activated protein kinase kinase 1394Homo sapiensMutation(s): 2 
Gene Names: MAP2K1MEK1PRKMK1
EC: 2.7.12.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02750 (Homo sapiens)
Explore Q02750 
Go to UniProtKB:  Q02750
PHAROS:  Q02750
GTEx:  ENSG00000169032 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ANP
Query on ANP

Download Ideal Coordinates CCD File 
C [auth A],
J [auth B]
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
C10 H17 N6 O12 P3
PVKSNHVPLWYQGJ-KQYNXXCUSA-N
A1AHE (Subject of Investigation/LOI)
Query on A1AHE

Download Ideal Coordinates CCD File 
I [auth B]N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1-benzopyran-3-yl}methyl)pyridin-2-yl]-N'-methylsulfuric diamide
C22 H18 F2 N4 O5 S
YQSZJOABXRROQR-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
H [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
L [auth B],
M [auth B],
N [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
NI
Query on NI

Download Ideal Coordinates CCD File 
E [auth A]NICKEL (II) ION
Ni
VEQPNABPJHWNSG-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
K [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.03α = 90
b = 107.95β = 90
c = 116.24γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-04-17
    Type: Initial release
  • Version 1.1: 2024-07-10
    Changes: Database references