Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography

Guetzoyan, Lucie; Ingham, Richard J.; Nikbin, Nikzad; Rossignol, Julien; Wolling, Michael; Baumert, Mark; Burgess-Brown, N.; Strain-Damerell, C.M.; Shrestha, L.; Brennan, P.E.; Fedorov, O.; Knapp, S.; Ley, Steven V.

doi:10.1039/c4md00007b

Cited by 43 publications

(34 citation statements)

References 27 publications

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“…Several BRD9-dircted efforts in discovery chemistry have been reported, [11–15] 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.…”

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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.

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confidence: 99%

Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

et al. 2017

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“…A similar approach has been followed in most systems reported to date, in which self-optimization has been implemented. These systems cover different areas of chemistry: polymerization reaction [13 ,14 ], heterogeneous catalytic processes [1,2,5], droplet formation [15,16] assembly of nanoparticles [17] and even multi-step syntheses [4,[18][19][20][21]. As we shall show below, this approach to automation is readily extendable to include chemoinformatics and design of experiments, using data exchange standards, such as OPC.…”

Section: Hardware For Self-optimization Of Closed-loop Systems Labwarementioning

confidence: 98%

Automatic discovery and optimization of chemical processes

Houben

Lapkin

2015

Current Opinion in Chemical Engineering

104

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This paper presents the first overview of recent developments in techniques and methods that enable closed-loop optimization, also sometimes called 'self optimization', as well as discovery in different areas of molecular sciences. The closed-loop experimental platforms offer tremendous new opportunities by significantly increasing productivity, as well as enabling completely new types of experiments to be performed. Such experiments involve three main enabling technology areas: automated experimental systems, analytical instruments connected to automated chemoinformatics software and optimization or decision-making algorithms. We review the most exciting developments concerning robotic experiments, 3D printed lab-ware, experimental systems with multiple analytical instruments and advanced optimization algorithms based on machine learning approaches. A range of different chemical problems is described, which show the breadth of potential applications of this emerging experimental approach.

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“…Highly homologous bromodomain containing protein 7 (BRD7) is a component of the SWI/SNF polybromoassociated BAF (PBAF) complex and has been proposed as a tumor suppressor [30]. Within the last year, there have been several publications focussing on BRD9 and dual BRD7/9 chemical probe development [31][32][33].…”

Section: Brd7 and Brd9mentioning

confidence: 99%

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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Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography

Abstract: Novel technologies were developed and used for the synthesis and evaluation of new triazolopyridazine BRD9 inhibitors.

Cited by 43 publications

References 27 publications

Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands

Automatic discovery and optimization of chemical processes

Clinical progress and pharmacology of small molecule bromodomain inhibitors

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