PDBsum entry 6ujh

Transcription

PDB id: 6ujh

Contents

Protein chains

313 a.a.

Ligands

QBS ×2

SO4 ×3

DMS ×3

Waters ×919

PDB id:

6ujh

Name:

Transcription

Title:

Discovery of fragment-inspired heterocyclic benzenesulfonamides as inhibitors of the wdr5-myc interaction

Structure:

Wd repeat-containing protein 5. Chain: a, b. Synonym: bmp2-induced 3-kb gene protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: wdr5, big3. Expressed in: escherichia coli k-12. Expression_system_taxid: 83333

Resolution:

1.49Å R-factor: 0.148 R-free: 0.169

Authors:

J.Phan,S.W.Fesik

Key ref:

S.Chacón Simon et al. (2020). Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design. J Med Chem, 63, 4315-4333. PubMed id: 32223236 DOI: 10.1021/acs.jmedchem.0c00224

Date:

03-Oct-19 Release date: 15-Apr-20

Protein chains

P61964  (WDR5_HUMAN) -  WD repeat-containing protein 5 from Homo sapiens

Seq: 334 a.a.

Struc: 313 a.a.

DOI no: 10.1021/acs.jmedchem.0c00224

J Med Chem 63:4315-4333 (2020)

PubMed id: 32223236

Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design.

S.Chacón Simon, F.Wang, L.R.Thomas, J.Phan, B.Zhao, E.T.Olejniczak, J.D.Macdonald, J.G.Shaw, C.Schlund, W.Payne, J.Creighton, S.R.Stauffer, A.G.Waterson, W.P.Tansey, S.W.Fesik.

ABSTRACT

The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.