7M0K

HPK1 IN COMPLEX WITH COMPOUND 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.248 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.

Vara, B.A.Levi, S.M.Achab, A.Candito, D.A.Fradera, X.Lesburg, C.A.Kawamura, S.Lacey, B.M.Lim, J.Methot, J.L.Xu, Z.Xu, H.Smith, D.M.Piesvaux, J.A.Miller, J.R.Bittinger, M.Ranganath, S.H.Bennett, D.J.DiMauro, E.F.Pasternak, A.

(2021) ACS Med Chem Lett 12: 653-661

  • DOI: 10.1021/acsmedchemlett.1c00096
  • Primary Citation of Related Structures:  
    7M0L, 7M0M, 7M0K

  • PubMed Abstract: 
  • Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo , supporting its value as an immunotherapeutic target ...

    Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo , supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.


    Organizational Affiliation

    Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Pharmacokinetics and Drug Metabolism, Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts 02115, United States.



Macromolecules
Find similar proteins by:  (by identity cutoff)  |  Structure
Entity ID: 1
MoleculeChainsSequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase kinase 1A, B, C, D289Homo sapiensMutation(s): 0 
Gene Names: MAP4K1HPK1
EC: 2.7.11.1
Find proteins for Q92918 (Homo sapiens)
Explore Q92918 
Go to UniProtKB:  Q92918
NIH Common Fund Data Resources
PHAROS:  Q92918
Protein Feature View
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
YK7
Query on YK7

Download Ideal Coordinates CCD File 
E [auth A], F [auth B], G [auth C], H [auth D]4-anilino-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide
C22 H24 N6 O2
GECWYEGIHOUDQU-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.248 
  • R-Value Observed: 0.248 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.074α = 90.02
b = 76.627β = 97.02
c = 89.2γ = 89.98
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
REFMACphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Deposited Date: 2021-03-11 
  • Released Date: 2021-04-07 
  • Deposition Author(s): Lesburg, C.A.

Revision History  (Full details and data files)

  • Version 1.0: 2021-04-07
    Type: Initial release
  • Version 1.1: 2021-05-05
    Changes: Database references