8C78
Crystal structure of human BCL6 BTB domain in complex with compound CCT374705
Summary for 8C78
| Entry DOI | 10.2210/pdb8c78/pdb |
| Descriptor | B-cell lymphoma 6 protein, (2~{S})-10-[(3-chloranyl-2-fluoranyl-pyridin-4-yl)amino]-2-cyclopropyl-3,3-bis(fluoranyl)-7-methyl-2,4-dihydro-1~{H}-[1,4]oxazepino[2,3-c]quinolin-6-one, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | inhibitor, cancer, lymphoma, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 17268.97 |
| Authors | Le Bihan, Y.-V.,van Montfort, R.L.M. (deposition date: 2023-01-13, release date: 2023-04-26, Last modification date: 2024-06-19) |
| Primary citation | Harnden, A.C.,Davis, O.A.,Box, G.M.,Hayes, A.,Johnson, L.D.,Henley, A.T.,de Haven Brandon, A.K.,Valenti, M.,Cheung, K.J.,Brennan, A.,Huckvale, R.,Pierrat, O.A.,Talbot, R.,Bright, M.D.,Akpinar, H.A.,Miller, D.S.J.,Tarantino, D.,Gowan, S.,de Klerk, S.,McAndrew, P.C.,Le Bihan, Y.V.,Meniconi, M.,Burke, R.,Kirkin, V.,van Montfort, R.L.M.,Raynaud, F.I.,Rossanese, O.W.,Bellenie, B.R.,Hoelder, S. Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones. J.Med.Chem., 66:5892-5906, 2023 Cited by PubMed Abstract: B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and exposure of the non-degrading isomer, , of our recently published degrader, . The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of , a potent inhibitor of BCL6 with a good profile. Modest efficacy was achieved in a lymphoma xenograft mouse model after oral dosing. PubMed: 37026591DOI: 10.1021/acs.jmedchem.3c00155 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
Download full validation report
