4 research outputs found
Discovery of 1‑(1<i>H</i>‑Pyrazolo[4,3‑<i>c</i>]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers
The ERK/MAPK pathway
plays a central role in the regulation of
critical cellular processes and is activated in more than 30% of human
cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy
in patients for the treatment of BRAF-mutant melanoma. However, the
majority of responses are transient, and resistance is often associated
with pathway reactivation of the ERK signal pathway. Acquired resistance
to these agents has led to greater interest in ERK, a downstream target
of the MAPK pathway. De novo design efforts of a novel scaffold derived
from SCH772984 by employing hydrogen bond interactions specific for
ERK in the binding pocket identified 1-(1<i>H</i>-pyrazoloÂ[4,3-<i>c</i>]Âpyridin-6-yl)Âureas as a viable lead series. Sequential
SAR studies led to the identification of highly potent and selective
ERK inhibitors with low molecular weight and high LE. Compound <b>21</b> exhibited potent target engagement and strong tumor regression
in the BRAF<sup>V600E</sup> xenograft model
Discovery of 1‑(1<i>H</i>‑Pyrazolo[4,3‑<i>c</i>]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers
The ERK/MAPK pathway
plays a central role in the regulation of
critical cellular processes and is activated in more than 30% of human
cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy
in patients for the treatment of BRAF-mutant melanoma. However, the
majority of responses are transient, and resistance is often associated
with pathway reactivation of the ERK signal pathway. Acquired resistance
to these agents has led to greater interest in ERK, a downstream target
of the MAPK pathway. De novo design efforts of a novel scaffold derived
from SCH772984 by employing hydrogen bond interactions specific for
ERK in the binding pocket identified 1-(1<i>H</i>-pyrazoloÂ[4,3-<i>c</i>]Âpyridin-6-yl)Âureas as a viable lead series. Sequential
SAR studies led to the identification of highly potent and selective
ERK inhibitors with low molecular weight and high LE. Compound <b>21</b> exhibited potent target engagement and strong tumor regression
in the BRAF<sup>V600E</sup> xenograft model
Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry
Recent
advances in understanding the relevance of noncoding RNA
(ncRNA) to disease have increased interest in drugging ncRNA with
small molecules. The recent discovery of ribocil, a structurally distinct
synthetic mimic of the natural ligand of the flavin mononucleotide
(FMN) riboswitch, has revealed the potential chemical diversity of
small molecules that target ncRNA. Affinity-selection mass spectrometry
(AS-MS) is theoretically applicable to high-throughput screening (HTS)
of small molecules binding to ncRNA. Here, we report the first application
of the Automated Ligand Detection System (ALIS), an indirect AS-MS
technique, for the selective detection of small molecule–ncRNA
interactions, high-throughput screening against large unbiased small-molecule
libraries, and identification and characterization of novel compounds
(structurally distinct from both FMN and ribocil) that target the
FMN riboswitch. Crystal structures reveal that different compounds
induce various conformations of the FMN riboswitch, leading to different
activity profiles. Our findings validate the ALIS platform for HTS
screening for RNA-binding small molecules and further demonstrate
that ncRNA can be broadly targeted by chemically diverse yet selective
small molecules as therapeutics
Discovery of a 3‑(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
Leucine-rich repeat
kinase 2 (LRRK2) is a large, multidomain protein
which contains a kinase domain and GTPase domain among other regions.
Individuals possessing gain of function mutations in the kinase domain
such as the most prevalent G2019S mutation have been associated with
an increased risk for the development of Parkinson’s disease
(PD). Given this genetic validation for inhibition of LRRK2 kinase
activity as a potential means of affecting disease progression, our
team set out to develop LRRK2 inhibitors to test this hypothesis.
A high throughput screen of our compound collection afforded a number
of promising indazole leads which were truncated in order to identify
a minimum pharmacophore. Further optimization of these indazoles led
to the development of MLi-2 (<b>1</b>): a potent, highly selective,
orally available, brain-penetrant inhibitor of LRRK2