| Title: |
Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4 |
| Authors: |
Londregan, Allyn T.; Aitmakhanova, Karlygash; Bennett, James; Byrnes, Laura J.; Canterbury, Daniel P.; Cheng, Xiayun; Christott, Thomas; Clemens, Jennifer; Coffey, Steven B.; Dias, João M.; Dowling, Matthew S.; Farnie, Gillian; Fedorov, Oleg; Fennell, Kimberly F.; Gamble, Vicki; Gileadi, Carina; Giroud, Charline; Harris, Michael R.; Hollingshead, Brett D.; Huber, Kilian; Korczynska, Magdalena; Lapham, Kimberly; Loria, Paula M.; Narayanan, Arjun; Owen, Dafydd R.; Raux, Brigitt; Sahasrabudhe, Parag V.; Ruggeri, Roger B.; Sáez, Laura Díaz; Stock, Ingrid A.; Thuma, Benjamin A.; Tsai, Andy; Varghese, Alison E. |
| Contributors: |
European Commission; Londregan, Allyn T.; #NODATA#; Byrnes, Laura J.; Cheng, Xiayun; Dias, João M.; Dowling, Matthew S.; Huber, Kilian; Owen, Dafydd R.; Ruggeri, Roger B.; Varghese, Alison E. |
| Publisher Information: |
American Chemical Society |
| Publication Year: |
2023 |
| Collection: |
Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| Description: |
13 pages, 3 figures, 4 tables ; A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders. ; K.A., J.B., T.C., G.F., O.F., V.G., C.G., C.G., K.H., B.R., and L.D.S. received support from the EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant no 875510) for work conducted at the Centre for Medicines Discovery. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
#PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/EC/H2020/875510; https://doi.org/10.1021/acs.jmedchem.2c01421; No; Journal of Medicinal Chemistry 66(1): 460–472 (2023); https://hdl.handle.net/10261/416220; https://api.elsevier.com/content/abstract/scopus_id/85144806600 |
| DOI: |
10.1021/acs.jmedchem.2c01421 |
| Availability: |
https://hdl.handle.net/10261/416220; https://doi.org/10.1021/acs.jmedchem.2c01421; https://api.elsevier.com/content/abstract/scopus_id/85144806600 |
| Rights: |
info:eu-repo/semantics/closedAccess |
| Accession Number: |
edsbas.61503E48 |
| Database: |
BASE |