Protein Information: CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH COMPOUND-11 AKA 6-CYCLOPROPANEAMIDO-4-{[2-METHOXY-3-(1-METHYL-1H-1,2,4-TRI AZOL-3-YL)PHENYL]AMINO}-N-(?H?)METHYLPYRIDAZINE-3-CARBOXAMIDE

Key Attributes

Key Attributes

Attribute Value
UniProt ID P29597
Method X-RAY DIFFRACTION
Resolution 2.35 Å
R-factor Work 0.189
R-factor Free 0.238
Classification TRANSFERASE
Source Organism Homo sapiens
Number of Mutations 0
Sequence Length 317
Canonical Sequence MGSSHHHHHHSSGETVRFQGHMNLSQLSFHRVDQKEITQLSHLGQGTRTNVYEGRLRVEGSGDPEEGKMDDEDPLVPGRDRGQELRVVLKVLDPSHHDIALAFYETASLMSQVSHTHLAFVHGVCVRGPENIMVTEYVEHGPLDVWLRRERGHVPMAWKMVVAQQLASALSYLENKNLVHGNVCGRNILLARLGLAEGTSPFIKLSDPGVGLGALSREERVERIPWLAPECLPGGANSLSTAMDKWGFGATLLEICFDGEAPLQSRSPSEKEHFYQRQHRLPEPSCPQLATLTSQCLTYEPTQRPSFRTILRDLTRL
PubMed Abstract Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 ( 11 ) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.
Uniprot Link https://www.uniprot.org/uniprotkb/P29597/entry
Citations

Citations

  • Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165.
    DOI: 10.1021/acs.jmedchem.9b00444
    Authors: Wrobleski, S.T., Moslin, R., Lin, S., Zhang, Y., Spergel, S., Kempson, J., Tokarski, J.S., Strnad, J., Zupa-Fernandez, A., Cheng, L., Shuster, D., Gillooly, K., Yang, X., Heimrich, E., McIntyre, K.W., Chaudhry, C., Khan, J., Ruzanov, M., Tredup, J., Mulligan, D., Xie, D., Sun, H., Huang, C., D'Arienzo, C., Aranibar, N., Chiney, M., Chimalakonda, A., Pitts, W.J., Lombardo, L., Carter, P.H., Burke, J.R., Weinstein, D.S.
    Journal: J Med Chem 62 Pages: 8973-8995
    Year: 2019
Macromolecules

Macromolecules

Molecule Sequence Length Organism Chains
Non-receptor tyrosine-protein kinase TYK2 317 Homo sapiens A, B
Small Molecules

Small Molecules

Molecule ID Name Formula InChI Key Chains Author Identified Chains Binding Affinities SMILES
LB7 6-[(cyclopropanecarbonyl)amino]-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N-methylpyridazine-3-carboxamide C20 H22 N8 O3 BZZKEPGENYLQSC-UHFFFAOYSA-N C A
  • IC50: 0.14000000059604645 nM (Link)
  • IC50: 5.699999809265137 nM (Link)
  • IC50: 5.900000095367432 nM (Link)
  • IC50: 5.599999904632568 nM (Link)
  • EC50: 5.130000114440918 nM (Link)
  • EC50: 6.53000020980835 nM (Link)
  • IC50: 5.5 nM (Link)
CNC(=O)c1c(cc(nn1)NC(=O)C2CC2)Nc3cccc(c3OC)c4ncn(n4)C
CL CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M E B
  • IC50: 0.14000000059604645 nM (Link)
  • IC50: 5.699999809265137 nM (Link)
  • IC50: 5.900000095367432 nM (Link)
  • IC50: 5.599999904632568 nM (Link)
  • EC50: 5.130000114440918 nM (Link)
  • EC50: 6.53000020980835 nM (Link)
  • IC50: 5.5 nM (Link)
[Cl-]
Assemblies

Assemblies

Symmetry Kind Symmetry Type Symmetry Symbol Oligomeric State Modeled Polymer Monomer Count
Global Symmetry Cyclic C2 Homo 2-mer 519
Global Symmetry Asymmetric C1 Monomer 259
Global Symmetry Asymmetric C1 Monomer 260