Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance

Crawford, Terry D.; Vartanian, Steffan; Côté, Alexandre; Bellon, S.F.; Duplessis, Martin; Flynn, E. Megan; Hewitt, Michael C.; Huang, Hon-Ren; Kiefer, James R.; Murray, J.M.; Nasveschuk, Christopher G.; Pardo, Eneida; Romero, F. Anthony; Sandy, Péter; Tang, Yong; Taylor, Alexander M.; Tsui, Vickie; Wang, Jian; Wang, Shumei; Zawadzke, Laura E.; Albrecht, Brian K.; Magnuson, Steven; Cochran, Andrea G.; Stokoe, David

doi:10.1016/j.bmcl.2017.05.063

Cited by 35 publications

(36 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…53 Potent and selective inhibitors that bind to the BRD7/9 bromodomains have recently emerged from structure-guided medicinal chemistry campaigns, including compounds I-BRD9, 38 LP99, 54 ketone “compound 28 ”, 55 BI-7273 and BI-9564 56 ( 1a , b , Figure 1), and GNE-375. 57 These BRD7/9 inhibitors have been used in cells to help clarify the roles of the BRD7/9 bromodomains in oncogenesis and other disease states. For example, pharmacological studies of inhibitors 1a and 1b in combination with domain-swap protein engineering revealed that an active bromodomain of BRD9 is required to sustain MYC transcription and proliferation of leukemic cells.…”

Section: Introductionmentioning

confidence: 99%

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

et al. 2018

View full text Add to dashboard Cite

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase–target pair deemed unsuitable: the von Hippel–Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure–activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target–ligase combinations.

show abstract

Section: Introductionmentioning

confidence: 99%

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

et al. 2018

View full text Add to dashboard Cite

show abstract

“…It is over-expressed in cervical cancer [12], promotes MYC expression and cell proliferation in acute myeloid leukemia [13]. Protein-engineering and inhibitor studies targeting BRD9 have shown promise in overcoming epigeneticallydefined drug resistance [14], and single or combinatorial effects of BRD9 inhibitors with doxorubicin or carboplatin also resulted in anti-proliferative effects in five malignant rhabdoid tumor cell lines [15]. Risdom et al revealed that epigenetic plasticity mediated by the chromatin modifier BRD4 drives survival of triple-negative breast cancer cells after targeted therapy treatment [16].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer

et al. 2020

View full text Add to dashboard Cite

Neoadjuvant chemotherapy is given before surgery to patients with primarily unresectable, advanced-stage cancers to render the tumor resectable, and to facilitate breast conservation. Previously, we have reported a prospective phase II trial for women with stage IIA-B/IIIA-B-C breast cancer with improved pathologic complete response (pCR) when using bevacizumab in the neoadjuvant setting. Chemotherapy agents are given intravenously during multiple cycles of systemic treatments. However, the effect of the treatment is only evaluated upon the completion of therapy. Here, data from a clinical trial of 40 breast cancer patients with very aggressive disease and poor prognosis were studied aiming to identify epigenetic signatures in blood-derived DNA at baseline as potential non-invasive markers to predict pCR and to determine if treatment-related changes inepigenetic profiles reflect responsiveness to therapy. We performed genome-wide DNA methylation profiling using blood-derived DNA, and found that pre-treatment methylation status of BRD9 was predictive of responsiveness to therapy. Post-treatment global methylation differences were also observed between responders and non-responders. Most differentially methylated (DM) CpGs were located in promoter CpG-island regions for responders and in the open-sea region for non-responders. In responders, DNMT3B was hypomethylated while most of the other genes were hypermethylated after 4 cycles of treatment. Hypomethylation of DNMT3B could potentially lead to the increased methylation of oncogenes and genes responsible for cell growth and proliferation, facilitating responsiveness to the therapy. These results support the possible development of BRD9 as a biomarker for treatment selection before neoadjuvant therapy with chemotherapy and bevacizumab, and indicate DNMT3B as a potential target to improve clinical response. Further prospective validation of these findings is warranted.

show abstract

“…Additionally,s ubstitutionf rom the ortho and meta positions of the benzene ring wash ypothesized to occupy as mall pocket in BRD9, further enhancing selectivity,e ventually leading to GNE-375 (64). [87] Compound 64 exhibited potency at BRD9 (pIC 50 = 8.3) and > 3000fold selectivity over the BET bromodomains (BRD4(1) pIC 50 = < 4.7) as measured by TR-FRET assays. Potency (BRD9 pK D = 8.7) and selectivity against other non-BET bromodomains was also confirmed using aB ROMOscan panel with > 1500-fold selectivity observed against the panel,e xcluding the highly homologous BRD7 (pK D = 7.0) where 50-folds electivity was observed.…”

Section: Brd7/9mentioning

confidence: 96%

Advancements in the Development of non‐BET Bromodomain Chemical Probes

et al. 2019

View full text Add to dashboard Cite

The bromodomain and extra terminal (BET) family of bromodomain‐containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high‐quality chemical probes for their tandem bromodomains. In turn, these chemical probes have helped reveal the profound biological role of the BET bromodomains and their role in disease, ultimately leading to a number of molecules in active clinical development. However, the BET subfamily represents just 8/61 of the known human bromodomains, and attention has now expanded to the biological role of the remaining 53 non‐BET bromodomains. Rapid growth of this research area has been accompanied by a greater understanding of the requirements for an effective bromodomain chemical probe and has led to a number of new non‐BET bromodomain chemical probes being developed. Advances since December 2015 are discussed, highlighting the strengths/caveats of each molecule, and the value they add toward validating the non‐BET bromodomains as tractable therapeutic targets.

show abstract

Inhibition of bromodomain-containing protein 9 for the prevention of epigenetically-defined drug resistance

Cited by 35 publications

References 33 publications

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer

Advancements in the Development of non‐BET Bromodomain Chemical Probes

Contact Info

Product

Resources

About