2. Academic Validation
  3. Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4

  • J Med Chem. 2023 Jan 12;66(1):460-472. doi: 10.1021/acs.jmedchem.2c01421.
Allyn T Londregan 1,  Karlygash Aitmakhanova 2,  James Bennett 2,  Laura J Byrnes 3,  Daniel P Canterbury 3,  Xiayun Cheng 4,  Thomas Christott 2,  Jennifer Clemens 3,  Steven B Coffey 3,  João M Dias 3,  Matthew S Dowling 3,  Gillian Farnie 2,  Oleg Fedorov 2,  Kimberly F Fennell 3,  Vicki Gamble 2,  Carina Gileadi 2,  Charline Giroud 2,  Michael R Harris 3,  Brett D Hollingshead 4,  Kilian Huber 2,  Magdalena Korczynska 4,  Kimberly Lapham 3,  Paula M Loria 3,  Arjun Narayanan 4,  Dafydd R Owen 4,  Brigitt Raux 2,  Parag V Sahasrabudhe 3,  Roger B Ruggeri 3,  Laura Díaz Sáez 2,  Ingrid A Stock 3,  Benjamin A Thuma 3,  Andy Tsai 3,  Alison E Varghese 3
Affiliations

Affiliations

  • 1 Pfizer Medicine Design, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
  • 2 Centre for Medicines Discovery, NDM, University of Oxford, Oxford OX3 7DQ, U.K.
  • 3 Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.
  • 4 Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
PMID: 36562986 DOI: 10.1021/acs.jmedchem.2c01421
Abstract

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.

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