{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Harnden AC"],"funding":["NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research","Cancer Research UK","CRT Pioneer Fund","Sixth Element Capital"],"pagination":["5892-5906"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10150366"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["66(8)"],"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 <i>in vivo</i> exposure of the non-degrading isomer, <b>CCT373567</b>, of our recently published degrader, <b>CCT373566</b>. 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 <b>CCT374705</b>, a potent inhibitor of"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Discovery of an <i>In Vivo</i> Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones."],"pmcid":["PMC10150366"],"funding_grant_id":["C309/A11566"],"pubmed_authors":["Valenti M","Meniconi M","Harnden AC","Pierrat OA","Bellenie BR","Hoelder S","Box GM","de Haven Brandon AK","Huckvale R","Tarantino D","de Klerk S","Davis OA","Cheung KJ","Hayes A","Burke R","Miller DSJ","Kirkin V","Bright MD","Talbot R","van Montfort RLM","Raynaud FI","Johnson LD","Akpinar HA","Gowan S","Henley AT","Brennan A","Rossanese OW","McAndrew PC","Le Bihan YV"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of an <i>In Vivo</i> Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.","description":"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 <i>in vivo</i> exposure of the non-degrading isomer, <b>CCT373567</b>, of our recently published degrader, <b>CCT373566</b>. 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 <b>CCT374705</b>, a potent inhibitor of","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Apr","modification":"2026-05-29T03:06:31.685Z","creation":"2025-02-19T02:37:51.101Z"},"accession":"S-EPMC10150366","cross_references":{"pubmed":["37026591"],"doi":["10.1021/acs.jmedchem.3c00155"]}}