4 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
Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR)
A novel series of small-molecule
inhibitors has been developed
to target the double mutant form of the epidermal growth factor receptor
(EGFR) tyrosine kinase, which is resistant to treatment with gefitinib
and erlotinib. Our reported compounds also show selectivity over wild-type
EGFR. Guided by molecular modeling, this series was evolved to target
a cysteine residue in the ATP binding site via covalent bond formation
and demonstrates high levels of activity in cellular models of the
double mutant form of EGFR. In addition, these compounds show significant
activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to
their observed clinical efficacy. A glutathione (GSH)-based assay
was used to measure thiol reactivity toward the electrophilic functionality
of the inhibitor series, enabling both the identification of a suitable
reactivity window for their potency and the development of a reactivity
quantitative structure-property relationship (QSPR) to support design
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
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
The
biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was
identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic
substituents replacing the <i>N</i>-methyl group were designed
directing toward the conserved bromodomain water pocket, and two distinct
binding conformations were then observed. The substituents either
directly displaced and rearranged the conserved solvent network, as
in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent
to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct
substituents for individual bromodomains provided selectivity handles
useful for future lead optimization efforts for selective BRD9, CECR2,
and TAF1(2) inhibitors