Through regulation of the epigenome,
the bromodomain and extra
terminal (BET) family of proteins represent important therapeutic
targets for the treatment of human disease. Through mimicking the
endogenous N-acetyl-lysine group and disrupting the
protein–protein interaction between histone tails and the bromodomain,
several small molecule pan-BET inhibitors have progressed to oncology
clinical trials. This work describes the medicinal chemistry strategy
and execution to deliver an orally bioavailable tetrahydroquinoline
(THQ) pan-BET candidate. Critical to the success of this endeavor
was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors
within the GSK collection which enabled identification of appropriate
lipophilicity space to deliver compounds with a higher probability
of desired oral candidate quality properties. SAR knowledge was leveraged
via Free–Wilson analysis within this design space to identify
a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy
in mouse models of oncology and inflammation.
The
bromodomain and extra terminal (BET) family of proteins
are
an integral part of human epigenome regulation, the dysregulation
of which is implicated in multiple oncology and inflammatory diseases.
Disrupting the BET family bromodomain acetyl-lysine (KAc) histone
protein–protein interaction with small-molecule KAc mimetics
has proven to be a disease-relevant mechanism of action, and multiple
molecules are currently undergoing oncology clinical trials. This
work describes an efficiency analysis of published GSK pan-BET bromodomain
inhibitors, which drove a strategic choice to focus on the identification
of a ligand-efficient KAc mimetic with the hypothesis that lipophilic
efficiency could be drastically improved during optimization. This
focus drove the discovery of the highly ligand-efficient and structurally
distinct benzoazepinone KAc mimetic. Following crystallography to
identify suitable growth vectors, the benzoazepinone core was optimized
through an explore-exploit structure–activity relationship
(SAR) approach while carefully monitoring lipophilic efficiency to
deliver I-BET432 (41) as an oral candidate quality molecule.
Background
SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation.
Results
We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa.
Conclusions
This study identifies SP140 as a druggable epigenetic therapeutic target for CD.
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