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; Möbitz, Henrik; Ntaganda, Rukundo; Smith, Troy; Visser, M.; Hill, Susan E.; Hurtado, Felipe K.; Chenail, Gregg; Bhang, Hyo-eun C.; Bric, Anka; Xiang, Kay X.; Bushold, Geoffrey; Gilbert, Tamara J.; Vattay, Anthony; Dooley, Julie; Costa, Emily; Park, Isabel; Li, Ailing; Farley, David; Lounkine, Eugen; Yue, Qingxia; Xie, Xin; Zhu, Xiaoping; Kulathila, Raviraj; King, Daniel; Hu, Tiancen; Vulic, Katarina; Cantwell, John; Luu, Catherine A.; Jagani, Zainab

doi:10.1021/acs.jmedchem.8b01318

Cited by 134 publications

(131 citation statements)

References 36 publications

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“…Given that the ATPase, but not the bromodomain activity of BRM is central in driving the growth of BRG1-deficient cancer cells (14), we initiated a small molecule hit finding and validation strategy focused on DNA-dependent ATP hydrolysis driven by a truncated yet catalytically active version of BRM (ATPase-SnAC 636-1331) ((22) and (Fig. 1a).…”

Section: Resultsmentioning

confidence: 99%

“…The experiment was run in duplicate and data shown is mean ± SEM. c, chemical structures of BRM011 and BRM014 (Compounds 11 and 14 (22)) d and e, Correlation plot of BRM ATPase-SnAC (x-axis) IC 50 ’s against d, full length BRM and e, full length BRM/SNF5/BAF155/ BAF170 (y-axis) IC 50 ’s for a series of urea analogs. BRM011 and BRM014 are highlighted and the IC 50 curve for BRM011 is included as an inset in each plot.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, targeting SWI/SNF catalytic function with small molecule inhibitors has become highly attractive (18–21). In this work, we critically investigate the pharmacological activity of novel dual inhibitors of BRM and BRG1 ATPase function complementary to our recent description focused on their chemical optimization (22). Following the establishment of correlating biochemical, cellular pharmacodynamic and anti-proliferative activity of the compounds, we further validated their activity through the discovery of compound-resistant mutations, genome wide chromatin accessibility and transcriptional profiling, as well as surveying anti-proliferative activity in a large panel of BRG1 -mut vs. wild type lung cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

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In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Jagani

Chenail

Xiang

et al. 2019

Preprint

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Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of ontarget activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1-mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1-mut lung cancers.Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts. 0

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Jagani

Chenail

Xiang

et al. 2019

Preprint

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“…These observations led us to test the possibility that an inhibitor of a specialized function of BAF complexes might synergize with ATR inhibitors, allowing them to be used at lower, less toxic concentrations in the treatment of cancer. General inhibitors of BRG1/BRM ATPases have been described 21,22 but because the loss of BRG1 is lethal in nearly all cell types, they are likely far too toxic for therapeutic use. In addition, an inhibitor of the bromodomain of BRG1/SMARCA4 has been described, but is not effective at inhibiting cancer cell growth 20 .…”

Section: Discussionmentioning

confidence: 99%

“…A class of phospho-aminoglycosides (phospho-kanamycin) inhibits the yeast SWI2/SNF2 complex but also have limited utility in mammalian cells, are relatively non-specific ATPase inhibitors, and would likely be highly toxic in this context 21 . Recently, a BRG1 ATPase inhibitor was discovered 22 , yet its non-specific inhibition of both BRG1 and BRM would likely be toxic in patients due to the essential nature of the core ATPase subunits in cellular viability in many cell types. 10 As members of the thrithorax group proteins, mSWI/SNF complexes are generally thought to be activators of transcription.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing

Chory

Kirkland

Chang

et al. 2019

Preprint

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SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer. Figure 1: Strategy for assessing hyper-synthetic lethality of combination BD98 and ATRi (A) Macromolecular assembly of SWI/SNF complexes. BAF/PBAF-specific subunits labelled in blue/red respectively. (B) Workflow of screen used to identify putative BAF inhibitors. (C) Structure of BD98. (D) Summary of results (combination index scores, normalized isobolograms) obtained in Chou-Talalay method for assessment of synergy

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Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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2023

Encyclopedia of Life Sciences

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Vital processes such as transcription, repair, replication and recombination continuously shape cellular chromatin landscape. The chromodomain helicase DNA‐binding (CHD) family of enzymes regulate chromatin dynamics by utilising energy from ATP hydrolysis to alter nucleosomal position, structure and composition, thereby modulating accessibility of the underlying DNA sequence. The CHD enzymes are highly conserved in evolution, and genetic studies in fungi, plants and animals demonstrate their critical roles in regulation of cellular identity and fate and organismal development. Advances in genomic studies over the past two decades led to the identification of frequent DNA copy‐number alterations, mutations and aberrant expression of CHDs in human malignancies and various disorders, highlighting their importance as relevant biomarkers or targets for therapeutic intervention. Key Concepts CHD family of enzymes (CHD1‐9) are evolutionary conserved ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes, such as transcription, replication and repair. They are critical for normal organismal development and are frequently mutated in human disorders and cancers. Chromodomain helicase DNA‐binding proteins (CHD1‐9) are evolutionary conserved family of ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes such as transcription, replication and DNA repair. CHD enzymes share a common domain structure: two N‐terminal chromodomains, a central ATPase/helicase domain, and a C‐terminal DNA‐binding domain. CHD proteins play crucial roles in diverse cellular processes, including embryonic development, stem cell maintenance and differentiation, and tissue‐specific gene expression. Dysregulation of CHD proteins has been associated with various human diseases, including cancer and neurodevelopmental disorders. CHD proteins are attractive targets for the development of new therapies for diseases associated with chromatin dysfunction. Understanding the molecular mechanisms underlying the function of CHD proteins may pave the way for the development of new drugs that target these proteins and improve the treatment of a variety of human diseases.

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

Cited by 134 publications

References 36 publications

In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing

Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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