Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055

Mayako Michino; Tanweer A Khan; Michael W Miller; Yoshiyuki Fukase; Jeremie Vendome; Carolina Adura; J Fraser Glickman; Yiman Liu; Liling Wan; C David Allis; Andrew W Stamford; Peter T Meinke; Louis M Renzetti; Stacia Kargman; Nigel J Liverton; David J Huggins

doi:10.1021/acsmedchemlett.4c00016

Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055

ACS Med Chem Lett. 2024 Mar 12;15(4):524-532. doi: 10.1021/acsmedchemlett.4c00016. eCollection 2024 Apr 11.

Authors

Mayako Michino¹, Tanweer A Khan¹, Michael W Miller¹, Yoshiyuki Fukase¹, Jeremie Vendome², Carolina Adura³, J Fraser Glickman³, Yiman Liu⁴, Liling Wan⁴, C David Allis⁵, Andrew W Stamford¹, Peter T Meinke^{1

6}, Louis M Renzetti⁷, Stacia Kargman^{1

7}, Nigel J Liverton¹, David J Huggins^{1

8}

Affiliations

¹ Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
² Schrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United States.
³ Fisher Drug Discovery Resource Center, The Rockefeller University, New York, New York 10065, United States.
⁴ Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
⁵ Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York 10065, United States.
⁶ Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States.
⁷ Bridge Medicines, The Rockefeller University, 1230 York Avenue, Smith Hall Annex, C-Floor, New York, New York 10065, United States.
⁸ Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021, United States.

PMID: 38628784
PMCID: PMC11017412 (available on 2025-04-11)
DOI: 10.1021/acsmedchemlett.4c00016

Abstract

Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.

Grants and funding

R00 CA226399/CA/NCI NIH HHS/United States