PDBsum entry 6ton

Transcription

PDB id: 6ton

Contents

Protein chain

125 a.a.

Ligands

ALA-TRP-VAL-ILE-PRO-ALA

NR5

EDO ×2

Waters ×87

PDB id:

6ton

Name:

Transcription

Title:

Crystal structure of human bcl6 btb domain in complex with compound 25b

Structure:

B-cell lymphoma 6 protein. Chain: a. Synonym: bcl-6,b-cell lymphoma 5 protein,bcl-5,protein laz-3,zinc finger and btb domain-containing protein 27,zinc finger protein 51. Engineered: yes. Ala-trp-val-ile-pro-ala. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl6, bcl5, laz3, zbtb27, znf51. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Expression_system_variant: ai. Synthetic: yes. Synthetic construct.

Resolution:

2.36Å R-factor: 0.197 R-free: 0.232

Authors:

M.J.Rodrigues,Y.-V.Le Bihan,R.L.M.Van Montfort

Key ref:

B.R.Bellenie et al. (2020). Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. J Med Chem, 63, 4047-4068. PubMed id: 32275432 DOI: 10.1021/acs.jmedchem.9b02076

Date:

11-Dec-19 Release date: 22-Apr-20

Protein chain

P41182  (BCL6_HUMAN) -  B-cell lymphoma 6 protein from Homo sapiens

Seq: 706 a.a.

Struc: 125 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.9b02076

J Med Chem 63:4047-4068 (2020)

PubMed id: 32275432

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

B.R.Bellenie, K.J.Cheung, A.Varela, O.A.Pierrat, G.W.Collie, G.M.Box, M.D.Bright, S.Gowan, A.Hayes, M.J.Rodrigues, K.N.Shetty, M.Carter, O.A.Davis, A.T.Henley, P.Innocenti, L.D.Johnson, M.Liu, S.de Klerk, Y.V.Le Bihan, M.G.Lloyd, P.C.McAndrew, E.Shehu, R.Talbot, H.L.Woodward, R.Burke, V.Kirkin, R.L.M.van Montfort, F.I.Raynaud, O.W.Rossanese, S.Hoelder.

ABSTRACT

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazo 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol- 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2- 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-o 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-on 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.