Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is ...implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice.
The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a ...drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.
We recently reported the discovery of GSK2606414 (1), a selective first in class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which inhibited PERK activation in cells ...and demonstrated tumor growth inhibition in a human tumor xenograft in mice. In continuation of our drug discovery program, we applied a strategy to decrease inhibitor lipophilicity as a means to improve physical properties and pharmacokinetics. This report describes our medicinal chemistry optimization culminating in the discovery of the PERK inhibitor GSK2656157 (6), which was selected for advancement to preclinical development.
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly ...deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
structure: see text. The syntheses of the proposed structure of pyrinodemin A (1) and its cis double bond positional isomer (C15'-C16') in racemic form are described. The key reaction involved an ...intramolecular nitrone/double bond cycloaddition. Our results suggest that neither 1 nor its double positional isomer is the correct structure of pyrinodemin A
The syntheses of hachijodine B
1
, the proposed structure of ikimine B
2
and niphatesine D
3
from
S-citronellol are described.
The syntheses of the proposed structures of hachijodine B
1
, ikimine B
...2
and niphatesine D
3
from
S-citronellol are described. Our results suggest that the gross structures of hachijodine B and niphatesine D are correct, but that ikimine B was incorrectly assigned. We have also established that the previous absolute stereochemical assignment for niphatesine D is unreliable.
The elucidation of the structure of the cytotoxic marine sponge alkaloid pyrinodemin A by synthesis is described. Based on the
13C NMR spectra of three double bond positional isomers and the natural ...product, it is concluded the C14′–C15′ isomer best represents the true structure of pyrinodemin A. In addition, the structural assignment of pyrinodemin C is evaluated.
The structure of the cytotoxic marine sponge alkaloid pyrinodemin A is best represented as
3
.
The absolute configuration of the marine sponge alkaloid pyrinodemin A is established by organic synthesis.
The absolute stereochemistry of the marine sponge alkaloid pyrinodemin A is established to ...be (15
S,16
S,20
R) through the asymmetric synthesis of
(−)-
3
.
An alternative possible structure of pyrinodemin A is synthesised. The
13C NMR of the synthetic product
3
is in better agreement with the literature data.
The synthesis of structure
3
is described.
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