Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers

被引：1

作者：

Vaswani, Rishi G. ^{[1
,2
]}

Huang, David S. ^{[1
]}

Anthony, Neville ^{[1
,3
]}

Xu, Lan ^{[1
,4
]}

Centore, Richard ^{[1
,5
]}

Schiller, Shawn ^{[1
]}

Li, Zhifang ^{[1
]}

Fan, Hong ^{[1
,6
]}

Setser, Jeremy ^{[1
,7
]}

Zawadzke, Laura E. ^{[1
,8
]}

Davenport, Yunji ^{[1
]}

Chen, Xueying ^{[1
,9
]}

Barnash, Kimberly ^{[1
,10
]}

Adam, Ammar ^{[1
]}

Ichikawa, Kana ^{[1
]}

Huang, Liyue ^{[1
,11
]}

Gu, Chong-Hui ^{[1
]}

Voigt, Johannes ^{[1
,12
]}

Millan, David ^{[1
,13
]}

Chan, Ho Man ^{[1
,14
]}

Decicco, Carl ^{[1
,15
]}

Hentemann, Martin ^{[1
]}

Bellon, Steven F. ^{[1
]}

Wilson, Kevin J. ^{[1
]}

机构：

[1] Foghorn Therapeut, Cambridge, MA 02139 USA

[2] Recludix Pharm, Cambridge, MA 02142 USA

[3] Enko Chem, Woburn, MA 01801 USA

[4] K36 Therapeut, Cambridge, MA 02142 USA

[5] Transit Bio, Watertown, MA 02472 USA

[6] BeiGene, Cambridge, MA 02142 USA

[7] Flare Therapeut, Cambridge, MA 02142 USA

[8] Lifemine Therapeut, Cambridge, MA 02140 USA

[9] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[10] Anagenex, Lexington, MA 02421 USA

[11] Vigil Neurosci, Watertown, MA 02472 USA

[12] Stackchem LLC, Philadelphia, PA 19067 USA

[13] Auron Therapeut, Newton, MA 02458 USA

[14] Astrazeneca, Waltham, MA 02451 USA

[15] Flagship Pioneering, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 02期

关键词：

MECHANISMS; RECEPTOR;

D O I：

10.1021/acs.jmedchem.4c02535

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive ATPase subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is an attractive therapeutic target because of its role in transcription, and mutations in the subunits of BAF are common in cancer and neurological disorders. Herein, we report the discovery of compound 1 (FHD-286) as a potent allosteric inhibitor of the dual ATPase subunits from a high-throughput screening hit with a BRM IC50 of similar to 27 mu M. FHD-286 is an orally bioavailable compound with antitumor activity in mouse xenograft models of uveal melanoma and acute myeloid leukemia and is being evaluated in Phase 1 clinical trials.

引用

页码：1772 / 1792

页数：21

共 1 条

[1] Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers
Papillon, Julien P. N.
Nakajima, Katsumasa
Adair, Christopher D.
Hempel, Jonathan
Jouk, Andriana O.
Karki, Rajeshri G.
Mathieu, Simon
Mobitz, Henrik
Ntaganda, Rukundo
Smith, Troy
Visser, Michael
Hill, Susan E.
Hurtado, Felipe Kellermann
Chenail, Gregg
Bhang, Hyo-Eun C.
Bric, Anka
Xiang, Kay
Bushold, Geoffrey
Gilbert, Tamara
Vattay, Anthony
Dooley, Julie
Costa, Emily A.
Park, Isabel
Li, Ailing
Farley, David
Lounkine, Eugen
Yue, Q. Kimberley
Xie, Xiaoling
Zhu, Xiaoping
Kulathila, Raviraj
King, Daniel
Hu, Tiancen
Vulic, Katarina
Cantwell, John
Luu, Catherine
Jagani, Zainab
JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (22) : 10155 - 10172

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