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
  • 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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