Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Gehling, Victor S.; Hewitt, Michael C.; Vaswani, Rishi G.; Leblanc, Yves; Côté, Alexandre; Nasveschuk, Christopher G.; Taylor, Alexander M.; Harmange, Jean-Christophe; Audia, James E.; Pardo, Eneida; Joshi, Shivangi; Sandy, Péter; Mertz, Jennifer A.; Sims, Robert J.; Bergeron, Louise; Bryant, Barbara M.; Bellon, S.F.; Poy, Florence; Jayaram, Hariharan; Sankaranarayanan, Ravichandran; Yellapantula, Sreegouri; Srinivasamurthy, Nandana Bangalore; Birudukota, Swarnakumari; Albrecht, Brian K.

doi:10.1021/ml4001485

Cited by 95 publications

(94 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The limitation to methyl at the 4 position is in contrast to what we observed with the isoxazolo [5,4-c]thieno [2,3-e]azepine scaffold (cf. CPI-3) 13 and with what others have observed with related scaffolds. 4,5 Substitutions at other positions of the benzo ring or at the 1 position of the isoxazole diminished potency (data not shown).…”

supporting

confidence: 83%

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Taylor

Vaswani

Gehling

et al. 2015

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo [b]isoxazolo [4,5-d] T he bromodomain and extra terminal (BET) family is made up of BRD2, BRD3, BRD4, and BRDT, each of which contains tandem bromodomains (BD-1 and BD-2) that recognize specific acetylated lysine residues in the N-terminal tails of histones. 1 Members of the BET family modulate gene expression by recruiting transcriptional regulators to specific genomic locations. 2 In 2009, the Mitsubishi Tanabe Pharma Corporation reported the first small molecule inhibitors of this family of chromatin adaptors, 3 and publications followed on the use of BET inhibitors to demonstrate antitumor activity 4 and modulate inflammation. 5 Experiments applying genetic ablation or specific inhibitor treatment have established the role of BET family members in regulating genes crucial for normal cell growth. 6−8 Subsequent studies 9,10 have defined a mechanistic link between potency of BET inhibition and activity against hematologic malignancies and demonstrated that BET inhibition regulates the MYC oncogene, resulting in cell cycle arrest and apoptosis. In vivo BET bromodomain inhibition leads to efficacy in xenograft models representing multiple cancer types, and BET bromodomains are also implicated in nononcology indications, i.e., human immunodeficiency virus and human t-lymphotrophic viral gene expression, DNA damage response, and cardiac hypertrophy. Importantly, BET inhibitors have been shown to selectively regulate a subset of multiple inflammatory cytokines, including interleukins 6, 1β, 17, 21, and 23, and granulocyte macrophage colony-stimulating factor 11,12 and have demonstrated efficacy in several in vivo models of inflammation, including endotoxic shock, experimental autoimmune encephalomyelitis, and arthritis. 5,11 Because of the potential therapeutic application of BET inhibition, we initiated a drug discovery program and recently reported on a fragment-based effort that resulted in a series of isoxazolo [5,4-c]thieno[2,3-e]azepine BET inhibitors exemplified by CPI-3 (Scheme 1). 13 Concurrent with that effort we were interested in exploring a different connectivity within the seven-membered ring that would provide a unique basis for modulation of the physicochemical properties and BET potency of the resultant compounds. Specifically, we hypothesized that changing the cyclic imine to a substituted aniline would retain the concave shape important for specific binding to the bromodomain while providing a different metabolic profile for the series. We were also interested in evaluating a modified linker in combination with the reported triazole binding element 4,5 and in finding a replacement for the thiophene group of CPI-3 because of its potential metabolic instability. Here we describe the resulting benzo [b]isoxazolo- [4,5-d]azepi...

show abstract

supporting

confidence: 83%

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Taylor

Vaswani

Gehling

et al. 2015

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

show abstract

“…tetrahydroquinolin-6-yl)benzoic Acid(34). Method B was used to couple methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and (4-chlorophenyl)-boronic acid.…”

mentioning

confidence: 99%

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

et al. 2014

View full text Add to dashboard Cite

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

show abstract

“…Primary screening techniques include protein-and ligandobserved nuclear magnetic resonance (NMR), X-ray crystallography, surface plasmon resonance, thermal shift assay (TSA), and biochemical assays. Notably, two-dimensional heteronuclear single quantum coherence (HSQC) NMR and X-ray crystallography, employed as frontline approaches at Abbott Laboratories (Abbott Park, IL, USA) and Astex Pharmaceuticals ( Cambridge, UK), respectively, deliver detailed information about fragment-binding modes at the earliest XiAP/ciAP1 primary screening and complex structure determination [62][63][64] HCv NS3 primary screening and complex structure determination 20 Bromodomain primary screening 73 and complex structure determination [71][72][73][74] Arf1-Arno complex structure determination 77 …”

Section: Ppi Screeningmentioning

confidence: 99%

“…68 The AcK pocket can bind selective small-molecule inhibitors with low nanomolar affinity, 69,70 and several efforts have been pursued to identify candidate inhibitors through FBDD. [71][72][73][74][75] In these studies, the fragment hits interact with conserved water molecules and residues by mimicking the AcK head group, whilst lipophilic parts of the fragments engage with hydrophobic side chains.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Fragment-based drug discovery and protein–protein interactions

Turnbull¹,

Boyd²,

Walse³

2014

RRBC

View full text Add to dashboard Cite

Protein-protein interactions (PPIs) are involved in many biological processes, with an estimated 400,000 PPIs within the human proteome. There is significant interest in exploiting the relatively unexplored potential of these interactions in drug discovery, driven by the need to find new therapeutic targets. Compared with classical drug discovery against targets with well-defined binding sites, developing small-molecule inhibitors against PPIs where the contact surfaces are frequently more extensive and comparatively flat, with most of the binding energy localized in "hot spots", has proven far more challenging. However, despite the difficulties associated with targeting PPIs, important progress has been made in recent years with fragmentbased drug discovery playing a pivotal role in improving their tractability. Computational and empirical approaches can be used to identify hot-spot regions and assess the druggability and ligandability of new targets, whilst fragment screening campaigns can detect low-affinity fragments that either directly or indirectly perturb the PPI. Once fragment hits have been identified and confirmed using biochemical and biophysical approaches, three-dimensional structural data derived from nuclear magnetic resonance or X-ray crystallography can be used to drive medicinal chemistry efforts towards the development of more potent inhibitors. A small-scale comparison presented in this review of "standard" fragments with those targeting PPIs has revealed that the latter tend to be larger, be more lipophilic, and contain more polar (acid/base) functionality, whereas three-dimensional descriptor data indicate that there is little difference in their three-dimensional character. These physiochemical properties can potentially be exploited in the rational design of PPI-specific fragment libraries and correlate well with optimized PPI inhibitors, which tend to have properties outside currently accepted guidelines for drug-likeness. Several examples of small-molecule PPI inhibitors derived from fragment-based drug discovery now exist and are described in this review, including navitoclax, a novel Bcl-2 family inhibitor which has entered Phase II clinical trials in patients with small-cell lung cancer and chronic lymphocytic leukemia.

show abstract

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Cited by 95 publications

References 25 publications

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

Fragment-based drug discovery and protein–protein interactions

Contact Info

Product

Resources

About

Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors

Cited by 95 publications

References 25 publications

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

Fragment-based drug discovery and protein&ndash;protein interactions

Contact Info

Product

Resources

About

Fragment-based drug discovery and protein–protein interactions