Discovery of a potent, orally available tricyclic derivative as a novel BRD4 inhibitor for melanoma.

Autor: Horai Y; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan. Electronic address: horai_eec@mii.maruho.co.jp., Suda N; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Uchihashi S; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Katakuse M; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Shigeno T; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Hirano T; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Takahara J; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Fujita T; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Mukoyama Y; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan., Haga Y; Research Department, Maruho Co., Ltd., Kyoto 600-8815, Japan.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Oct 01; Vol. 93, pp. 117461. Date of Electronic Publication: 2023 Aug 26.
DOI: 10.1016/j.bmc.2023.117461
Abstrakt: The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for cancer treatment. In this study, we outline the discovery of a novel BRD4 inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 inhibitor. However, it exhibited a poor pharmacokinetic (PK) profile. To address this, we conducted a scaffold-hopping procedure with derivative 1, which resulted in the creation of benzimidazolinone derivative 5. This new derivative displayed an improved PK profile. To further enhance the BRD4 inhibitory activity, we attempted to introduce hydrogen bond acceptors. This indeed improved the activity, but at the cost of decreased membrane permeability. Our search for a potent inhibitor with desirable permeability led to the development of tricyclic 18. This compound demonstrated powerful inhibitory activity and a favorable PK profile. More significantly, tricyclic 18 showed antitumor efficacy in a mouse melanoma xenograft model, suggesting that it holds potential as a therapeutic agent for melanoma treatment.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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