1256818-14-0Relevant articles and documents
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,M?bitz, 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
, p. 10155 - 10172 (2018/11/23)
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.
NOVEL PYRAZOLO PYRIMIDINE DERIVATIVES AND THEIR USE AS MALT1 INHIBITORS
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Page/Page column 92; 93, (2015/12/31)
The present invention describes new pyrazolo-pyrimidine derivatives of formula (I) or a pharmaceutically acceptable salt thereof; (I) wherein, R1 is halogen, cyano, or C1-C3alkyl optionally substituted by halogen; R2 is C1-C6alkyl optionally substituted one or more times by C1-C6alkyl, C2-C6alkenyl, hydroxyl, N,N-di-C1-C6alkyl amino, N-mono-C1-C6alkyl amino, O-Rg, Rg, phenyl, or by C1-C6alkoxy wherein said alkoxy again may optionally be substituted by C1-C6alkoxy, N,N-di-C1-C6alkyl amino, Rg or phenyl; C3-C6cycloalkyl optionally substituted by C1-C6alkyl, N,N-di-C1-C6alkyl amino or C1-C6alkoxy-C1-C6alkyl, and/or two of said optional substituents together with the atoms to which they are bound may form an annulated or spirocyclic 4 - 6 membered saturated heterocyclic ring comprising 1 - 2 O atoms; phenyl optionally substituted by C1-C6alkoxy; a 5 - 6 membered heteroaryl ring having 1 to 3 heteroatoms selected from N and O said ring being optionally substituted by C1-C6alkyl which may be optionally substituted by amino or hydroxy; Rg; or N,N-di-C1-C6alkyl amino carbonyl; and R is phenyl independently substituted two or more times by Ra, 2-pyridyl independently substituted one or more times by Rb, 3-pyridyl independently substituted one or more times by Rc, or 4-pyridyl independently substituted one or more times by Rd; which are generally interacting with MALT1 proteolytic and/or autoproteolytic activity, and in particular which may inhibit said activity. The present invention further describes the synthesis of said new pyrazolo-pyrimidine derivatives, their use as a medicament, especially by interacting with MALT1 proteolytic and/or autoproteolytic activity.
