2. Academic Validation
  3. Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers

  • J Med Chem. 2018 Nov 21;61(22):10155-10172. doi: 10.1021/acs.jmedchem.8b01318.
Julien P N Papillon,  Katsumasa Nakajima,  Christopher D Adair,  Jonathan Hempel,  Andriana O Jouk,  Rajeshri G Karki,  Simon Mathieu,  Henrik Möbitz 1,  Rukundo Ntaganda,  Troy Smith,  Michael Visser,  Susan E Hill,  Felipe Kellermann Hurtado,  Gregg Chenail,  Hyo-Eun C Bhang,  Anka Bric,  Kay Xiang,  Geoffrey Bushold,  Tamara Gilbert,  Anthony Vattay,  Julie Dooley,  Emily A Costa,  Isabel Park,  Ailing Li,  David Farley,  Eugen Lounkine,  Q Kimberley Yue,  Xiaoling Xie,  Xiaoping Zhu,  Raviraj Kulathila,  Daniel King,  Tiancen Hu,  Katarina Vulic,  John Cantwell 2,  Catherine Luu 2,  Zainab Jagani
Affiliations

Affiliations

  • 1 Global Discovery Chemistry , Novartis Institutes for Biomedical Research , Basel 4002 , Switzerland.
  • 2 Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
PMID: 30339381 DOI: 10.1021/acs.jmedchem.8b01318
Abstract

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different Cancer contexts and those of Other Diseases.

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