LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

Clark, Peter G. K.; Vieira, Lucas Campos Curcino; Tallant, C.; Fedorov, O.; Singleton, Dean; Rogers, Catherine; Monteiro, Octovia; Bennett, James M.; Baronio, Roberta; Müller, Susanne; Daniels, Danette L.; Méndez, Jacqui; Knapp, Stefan; Brennan, P.E.; Dixon, Darren J.

doi:10.1002/ange.201501394

Cited by 88 publications

(69 citation statements)

References 24 publications

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“…The SGC and the University of Oxford published LP99 (Fig. 4), a potent and selective inhibitor for both BRD9 and BRD7 bromodomains, which plays a role in regulating pro-inflammatory cytokine secretion 127 . Two other BRD9 inhibitors, BI-7273 and BI-9564, were described by Boehringer Ingelheim and the SGC (Fig.…”

Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

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Aberrations in the epigenetic landscape are a hallmark of cancer. Alterations in enzymes that are “writers,” “erasers,” or “readers” of histone modification marks are common. Bromodomains are “readers” that bind acetylated lysines in histone tails. Their most important function is the regulation of gene transcription by the recruitment of different molecular partners. Moreover, proteins containing bromodomains are also epigenetic regulators, although little is known about the specific function of these domains. In recent years, there has been increasing interest in developing small molecules that can target specific bromodomains. First, this has helped clarify biological functions of bromodomain-containing proteins. Secondly, it opens a new front for combatting cancer. In this review we will describe the structures and mechanisms associated with Bromodomain and Extra-Terminal motif (BET) inhibitors and non-BET inhibitors, their current status of development, and their promising role as anti-cancer agents.

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Section: Bromodomain Inhibitorsmentioning

confidence: 99%

Bromodomain inhibitors and cancer therapy: From structures to applications

2016

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“…[12,14,15] To explore the potential of bifunctional derivatives to induce BRD9 degradation, we initially selected as our starting point a close chemical analog of I-BRD9 described by GlaxoSmithKline (GSK-39). [14] This ligand was attractive in that it offered high binding affinity (IC50 = 7.9 nM) as well as a solvent exposed methoxy substituent amenable to chemical derivatization.…”

Section: Hhs Public Accessmentioning

confidence: 99%

“…Several BRD9-dircted efforts in discovery chemistry have been reported, [11][12][13][14][15] developing chemotypes for BRD9-specific engagement. A recent study further suggested BRD9 as a dependency in acute myeloid leukemia (AML), where bromodomain inhibition prompted a cytostatic response.…”

Section: Introductionmentioning

confidence: 99%

Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

et al. 2017

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The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10 to 100 fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound 6 (dBRD9) as a tool for the study of BRD9. Graphical abstractWith structural guidance alongside comparative biochemical and biological assays, an iterative design strategy resulted in the development of targeted small molecule degraders that rapidly, potently, and selectively eliminate BAF complex member BRD9. These first in class non-BET bromodomain degraders offer dramatic potency improvements over existing BRD9 probes in models of acute myloid leukemia.* james_bradner@dfci.harvard.edu; james.bradner@novartis.com.Supporting information for this article is given via a link at the end of the document. [4][5][6] Further, significant research effort has contributed a number of high quality chemical probes for bromodomain-containing proteins beyond the BET family. [7,8] The bromodomain-containing protein BRD9 has garnered particular attention as a component of the human ATP-dependent chromatin remodeling BAF complex (also known as SWI/SNF). Meta-analyses of whole-genome sequencing efforts have recently identified a high frequency of recurrent somatic mutations in BAF factors in diverse human cancers. [9] Within several subsets of these genetically defined malignancies, components of the BAF complex have emerged as context-specific dependencies, either supporting growth within a residual complex following loss of function mutation, or as novel oncogenes such as the SS18-SSX fusion. [10] These observations have generated interest in therapeutic strategies to target BAF. HHS Public AccessBeyond its presence in the BAF complex, a lack of functional annotation for BRD9 has provided incentive for development of BRD9 selective inhibitors to interrogate its biological role and to assess any therapeutic potential. Several BRD9-dircted efforts in discovery chemistry have been reported, [11][12][13][14][15] developing chemotypes for BRD9-specific engagement. A recent study further suggested BRD9 as a dependency in acute myeloid leukemia (AML), where bromodomain inhibition prompted a cytostatic response. [16] Beyond the bromodomain, the function of BRD9 remains unclear, and chemi...

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“…In parallel, research by the University of Oxford and the SGC, led to the discovery of LP99 (8) as the first reported dual BRD7/9 chemical probe(Figure 2a)[36]. Using fragment quinolone 7 as a start point, LP99 (8) was developed using structure-based design to guide introduction of a 4-methyl group to occupy a shallow hydrophobic pocket and a complex lactam to the quinolone 7-position to obtain the desired potency and selectivity(Figure 3b).…”

mentioning

confidence: 96%

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou¹,

Tomkinson

Prinjha

et al. 2016

Current Opinion in Chemical Biology

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Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders.

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LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

Cited by 88 publications

References 24 publications

Bromodomain inhibitors and cancer therapy: From structures to applications

Bromodomain inhibitors and cancer therapy: From structures to applications

Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

Clinical progress and pharmacology of small molecule bromodomain inhibitors

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