7 research outputs found
Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition
Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated OāH insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition
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 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
Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors
The identification of a novel series
of small molecule BET inhibitors is described. Using crystallographic
binding modes of an amino-isoxazole fragment and known BET inhibitors,
a structure-based drug design effort lead to a novel isoxazole azepine
scaffold. This scaffold showed good potency in biochemical and cellular
assays and oral activity in an in vivo model of BET inhibition
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