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 O–H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition

A Practical Synthesis of Indoles via a Pd-Catalyzed C–N Ring Formation

A method for the synthesis of <i>N</i>-functionalized C2-/C3-substituted indoles via Pd-catalyzed C–N bond coupling of halo-aryl enamines is described. The general strategy utilizes a variety of amines and β-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[4,3‑<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 benzo­[<i>b</i>]­isoxazolo­[4,5-<i>d</i>]­azepines and benzotriazolo­[4,3-<i>d</i>]­[1,4]­diazepines 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>)‑<i>N</i>‑((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)‑1<i>H</i>‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell 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 IC₅₀ = 0.002 μM, cellular EC₅₀ = 0.032 μM) 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