1819363-80-8Relevant articles and documents
Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit
Gerstenberger, Brian S.,Trzupek, John D.,Tallant, Cynthia,Fedorov, Oleg,Filippakopoulos, Panagis,Brennan, Paul E.,Fedele, Vita,Martin, Sarah,Picaud, Sarah,Rogers, Catherine,Parikh, Mihir,Taylor, Alexandria,Samas, Brian,O'Mahony, Alison,Berg, Ellen,Pallares, Gabriel,Torrey, Adam D.,Treiber, Daniel K.,Samardjiev, Ivan J.,Nasipak, Brian T.,Padilla-Benavides, Teresita,Wu, Qiong,Imbalzano, Anthony N.,Nickerson, Jeffrey A.,Bunnage, Mark E.,Müller, Susanne,Knapp, Stefan,Owen, Dafydd R.
, p. 4800 - 4811 (2016)
The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.
Novel structural-related analogs of PFI-3 (SRAPs) that target the BRG1 catalytic subunit of the SWI/SNF complex increase the activity of temozolomide in glioblastoma cells
He, Yali,Miller, Duane D.,Pfeffer, Lawrence M.,Sacher, Joshua R.,Sims, Michelle M.,Wang, Yinan,Yang, Chuanhe
, (2021/12/08)
Glioblastoma (GBM) is the most aggressive and treatment-refractory malignant adult brain cancer. After standard of care therapy, the overall median survival for GBM is only ～6 months with a 5-year survival 10%. Although some patients initially respond to the DNA alkylating agent temozolomide (TMZ), unfortunately most patients become resistant to therapy and brain tumors eventually recur. We previously found that knockout of BRG1 or treatment with PFI-3, a small molecule inhibitor of the BRG1 bromodomain, enhances sensitivity of GBM cells to temozolomide in vitro and in vivo GBM animal models. Those results demonstrated that the BRG1 catalytic subunit of the SWI/SNF chromatin remodeling complex appears to play a critical role in regulating TMZ-sensitivity. In the present study we designed and synthesized Structurally Related Analogs of PFI-3 (SRAPs) and tested their bioactivity in vitro. Among of the SRAPs, 9f and 11d show better efficacy than PFI-3 in sensitizing GBM cells to the antiproliferative and cell death inducing effects of temozolomide in vitro, as well as enhancing the inhibitor effect of temozolomide on the growth of subcutaneous GBM tumors.
BROMODOMAIN INHIBITORS TO TARGET THERAPY-RESISTANT CANCER
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Page/Page column 51; 54, (2021/03/05)
Novel inhibitors of the bromodomain of Brahma-related gene 1 (BRG1) are described. Also described are methods of treating glioblastoma using inhibitors of the BRG1 bromodomain in combination with chemotherapeutics, such as DNA alkylating agents. As described herein, the inhibitors sensitize glioblastoma cells, including chemoresistant glioblastoma cells, to DNA alkylating agents, for example, temozolomide and carmustine.
