6EW7

Crystal structure of the BCL6 BTB domain in complex with anilinopyrimidine ligand

Summary for 6EW7

• Entry DOI: 10.2210/pdb6ew7/pdb
• Related: 5N1X 5N1Z 5N20 5N21
• Descriptor: B-cell lymphoma 6 protein, CHLORIDE ION, 2-chloranyl-4-[[5-chloranyl-4-[(4-fluorophenyl)amino]pyrimidin-2-yl]amino]benzoic acid, ... (4 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 29058.13

Authors

Robb, G.,Ferguson, A.,Hargreaves, D. (deposition date: 2017-11-03, release date: 2018-10-24, Last modification date: 2024-05-08)

Primary citation

McCoull, W.,Cheung, T.,Anderson, E.,Barton, P.,Burgess, J.,Byth, K.,Cao, Q.,Castaldi, M.P.,Chen, H.,Chiarparin, E.,Carbajo, R.J.,Code, E.,Cowan, S.,Davey, P.R.,Ferguson, A.D.,Fillery, S.,Fuller, N.O.,Gao, N.,Hargreaves, D.,Howard, M.R.,Hu, J.,Kawatkar, A.,Kemmitt, P.D.,Leo, E.,Molina, D.M.,O'Connell, N.,Petteruti, P.,Rasmusson, T.,Raubo, P.,Rawlins, P.B.,Ricchiuto, P.,Robb, G.R.,Schenone, M.,Waring, M.J.,Zinda, M.,Fawell, S.,Wilson, D.M.
Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6.
ACS Chem. Biol., 13:3131-3141, 2018

PubMed Abstract: B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.

PubMed: 30335946
DOI: 10.1021/acschembio.8b00698

Experimental method

X-RAY DIFFRACTION (1.6 Å)