Development of potent dimeric inhibitors of GAS41 YEATS domain.

Autor:	Listunov D; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Linhares BM; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Kim E; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Winkler A; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Simes ML; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Weaver S; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Cho HJ; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Rizo A; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA., Zolov S; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2670, USA., Keshamouni VG; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2670, USA., Grembecka J; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA. Electronic address: jolantag@umich.edu., Cierpicki T; Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA. Electronic address: tomaszc@umich.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2021 Dec 16; Vol. 28 (12), pp. 1716-1727.e6. Date of Electronic Publication: 2021 Jul 21.
DOI:	10.1016/j.chembiol.2021.06.010
Abstrakt:	GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions. Competing Interests: Declaration of interests D.L., B.M.L., E.K., A.W., J.G., and T.C. are co-inventors on a patent application for GAS41 inhibitors. (Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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