6eg2
Crystal structure of human BRM in complex with compound 16
Structural highlights
DiseaseSMCA2_HUMAN Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358. A rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time.[1] [2] FunctionMALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.SMCA2_HUMAN Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).[3] Publication Abstract from PubMedSMARCA2 (SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2), also known as BRM (Brahma homolog) is a Snf2-family DNA-dependent ATPase. BRM, and its close homolog Brahma related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPase members of the large ATP-dependent SWI/SNF chromatin remodeling complexes involved in transcriptional regulation of gene expression. No small molecules modulating SWI/SNF chromatin remodeling activity via inhibition of its ATPase activity have been reported, 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 anti-proliferative 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 function more broadly in different cancer contexts and other diseases. Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/ SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2 (SMARCA2) ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/ SMARCA4-Mutant Cancers.,Papillon JPN, Nakajima K, Adair CD, Hempel J, Jouk AO, Karki R, Mathieu S, Moebitz H, Ntaganda R, Smith T, Visser M, Hill SE, Kellermann Hurtado F, Chenail G, Bhang HC, Bric A, Xiang K, Bushold G, Gilbert T, Vattay A, Dooley J, Costa EA, Park I, Li A, Farley D, Lounkine E, Yue QK, Xie X, Zhu X, Kulathila R, King D, Hu T, Vulic K, Cantwell J, Luu C, Jagani Z J Med Chem. 2018 Oct 19. doi: 10.1021/acs.jmedchem.8b01318. PMID:30339381[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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