10 research outputs found
A Practical Synthesis of Indoles via a Pd-Catalyzed CāN Ring Formation
A method for the
synthesis of <i>N</i>-functionalized
C2-/C3-substituted indoles via Pd-catalyzed CāN bond coupling
of halo-aryl enamines is described. The general strategy utilizes
a variety of amines and Ī²-keto esters which are elaborated into
halo-aryl enamines as latent precursors to indoles. The preferred
conditions comprising the RuPhos precatalyst and RuPhos in the presence
of NaOMe in 1,4-dioxane tolerate a variety of substituents and are
scalable for the construction of indoles in multigram quantities
Discovery and Optimization of Tetramethylpiperidinyl Benzamides as Inhibitors of EZH2
The identification and development
of a novel series of small molecule
Enhancer of Zeste Homologue 2 (EZH2) inhibitors is described. A concise
and modular synthesis enabled the rapid development of structureāactivity
relationships, which led to the identification of <b>44</b> as
a potent, SAM-competitive inhibitor of EZH2 that dose-dependently
decreased global H3K27me3 in KARPAS-422 lymphoma cells
Discovery of (<i>R</i>)ā6-(1-(8-Fluoro-6-(1-methylā1<i>H</i>āpyrazol-4-yl)-[1,2,4]triazolo[4,3ā<i>a</i>]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6<i>H</i>)āone (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity
Deregulation
of the receptor tyrosine kinase mesenchymal epithelial
transition factor (MET) has been implicated in several human cancers
and is an attractive target for small molecule drug discovery. Herein,
we report the discovery of compound <b>23</b> (AMG 337), which
demonstrates nanomolar inhibition of MET kinase activity, desirable
preclinical pharmacokinetics, significant inhibition of MET phosphorylation
in mice, and robust tumor growth inhibition in a MET-dependent mouse
efficacy model
Discovery of Benzotriazolo[4,3ā<i>d</i>][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains
Inhibition of the bromodomains of
the BET family, of which BRD4 is a member, has been shown to decrease
myc and interleukin (IL) 6 <i>in vivo</i>, markers that
are of therapeutic relevance to cancer and inflammatory disease, respectively.
Herein we report substituted benzoĀ[<i>b</i>]ĀisoxazoloĀ[4,5-<i>d</i>]Āazepines and benzotriazoloĀ[4,3-<i>d</i>]Ā[1,4]Ādiazepines
as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds
from these series were potent and selective in cells, and subsequent
optimization of microsomal stability yielded representatives that
demonstrated dose- and time-dependent reduction of plasma IL-6 in
mice
Identification of (<i>R</i>)ā<i>N</i>ā((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)ā1<i>H</i>āindole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for BāCell Lymphomas
Polycomb
repressive complex 2 (PRC2) has been shown to play a major
role in transcriptional silencing in part by installing methylation
marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates
with certain malignancies and poor prognosis. EZH2 is the catalytic
engine of the PRC2 complex and thus represents a key candidate oncology
target for pharmacological intervention. Here we report the optimization
of our indole-based EZH2 inhibitor series that led to the identification
of CPI-1205, a highly potent (biochemical IC<sub>50</sub> = 0.002
Ī¼M, cellular EC<sub>50</sub> = 0.032 Ī¼M) and selective
inhibitor of EZH2. This compound demonstrates robust antitumor effects
in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is
currently in Phase I clinical trials. Additionally, we disclose the
co-crystal structure of our inhibitor series bound to the human PRC2
complex
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)
CBP and EP300 are highly homologous,
bromodomain-containing transcription
coactivators involved in numerous cellular pathways relevant to oncology.
As part of our effort to explore the potential therapeutic implications
of selectively targeting bromodomains, we set out to identify a CBP/EP300
bromodomain inhibitor that was potent both <i>in vitro</i> and in cellular target engagement assays and was selective over
the other members of the bromodomain family. Reported here is a series
of cell-potent and selective probes of the CBP/EP300 bromodomains,
derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2<i>H</i>-benzoĀ[<i>b</i>]Ā[1,4]Ādiazepin-2-one
GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
Inhibition of the bromodomain of
the transcriptional regulator
CBP/P300 is an especially interesting new therapeutic approach in
oncology. We recently disclosed in vivo chemical tool <b>1</b> (GNE-272) for the bromodomain of CBP that was moderately potent
and selective over BRD4(1). In pursuit of a more potent and selective
CBP inhibitor, we used structure-based design. Constraining the aniline
of <b>1</b> into a tetrahydroquinoline motif maintained potency
and increased selectivity 2-fold. Structureāactivity relationship
studies coupled with further structure-based design targeting the
LPF shelf, BC loop, and KAc regions allowed us to significantly increase
potency and selectivity, resulting in the identification of non-CNS
penetrant <b>19</b> (GNE-781, TR-FRET IC<sub>50</sub> = 0.94
nM, BRET IC<sub>50</sub> = 6.2 nM; BRD4(1) IC<sub>50</sub> = 5100
nĪ) that maintained good in vivo PK properties in multiple species.
Compound <b>19</b> displays antitumor activity in an AML tumor
model and was also shown to decrease Foxp3 transcript levels in a
dose dependent manner
Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300
The single bromodomain of the closely
related transcriptional regulators
CBP/EP300 is a target of much recent interest in cancer and immune
system regulation. A co-crystal structure of a ligand-efficient screening
hit and the CBP bromodomain guided initial design targeting the LPF
shelf, ZA loop, and acetylated lysine binding regions. Structureāactivity
relationship studies allowed us to identify a more potent analogue.
Optimization of permeability and microsomal stability and subsequent
improvement of mouse hepatocyte stability afforded <b>59</b> (GNE-272, TR-FRET IC<sub>50</sub> = 0.02 Ī¼M, BRET IC<sub>50</sub> = 0.41 Ī¼M, BRD4(1) IC<sub>50</sub> = 13 Ī¼M) that retained
the best balance of cell potency, selectivity, and in vivo PK. Compound <b>59</b> showed a marked antiproliferative effect in hematologic
cancer cell lines and modulates <i>MYC</i> expression in
vivo that corresponds with antitumor activity in an AML tumor model