6 research outputs found
Additional file 3: Table S2. of De novo assembly and functional annotation of Myrciaria dubia fruit transcriptome reveals multiple metabolic pathways for L-ascorbic acid biosynthesis
Genic-SSR characteristics of M. dubia. (CSV 330 kb
Additional file 1: Table S1. of De novo assembly and functional annotation of Myrciaria dubia fruit transcriptome reveals multiple metabolic pathways for L-ascorbic acid biosynthesis
KEEG Pathway list in transcriptome of M. dubia. (CSV 6 kb
Additional file 5: Table S4. of De novo assembly and functional annotation of Myrciaria dubia fruit transcriptome reveals multiple metabolic pathways for L-ascorbic acid biosynthesis
SNPs in unigenes of M. dubia. (XLSX 2653 kb
Highly Potent Clickable Probe for Cellular Imaging of MDM2 and Assessing Dynamic Responses to MDM2-p53 Inhibition
MDM2
is a key negative regulator of the p53 tumor suppressor. Direct
binding of MDM2 to p53 represses the proteinâs transcriptional
activity and induces its polyubiquitination, targeting it for degradation
by the proteasome. Consequently, small molecule inhibitors that antagonize
MDM2-p53 binding, such as RG7388, have progressed into clinical development
aiming to reactivate p53 function in <i>TP53</i> wild-type
tumors. Here, we describe the design, synthesis, and biological evaluation
of a trans-cyclooctene tagged derivative of RG7388, RG7388-TCO, which
showed high cellular potency and specificity for MDM2. The in-cell
reaction of RG7388-TCO with a tetrazine-tagged BODIPY dye enabled
fluorescence imaging of endogenous MDM2 in SJSA-1 and T778 tumor cells.
RG7388-TCO was also used to pull down MDM2 by reaction with tetrazine-tagged
agarose beads in SJSA-1 lysates. The data presented show that RG733-TCO
enables precise imaging of MDM2 in cells and can permit a relative
assessment of target engagement and MDM2-p53 antagonism in vitro
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2
Aberrant activation of the MAPK pathway
drives cell proliferation
in multiple cancers. Inhibitors of BRAF and MEK kinases are approved
for the treatment of BRAF mutant melanoma, but resistance frequently
emerges, often mediated by increased signaling through ERK1/2. Here,
we describe the fragment-based generation of ERK1/2 inhibitors that
block catalytic phosphorylation of downstream substrates such as RSK
but also modulate phosphorylation of ERK1/2 by MEK without directly
inhibiting MEK. X-ray crystallographic and biophysical fragment screening
followed by structure-guided optimization and growth from the hinge
into a pocket proximal to the C-Îą helix afforded highly potent
ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant
cells, the lead compound suppresses pRSK and pERK levels and inhibits
proliferation at low nanomolar concentrations. The lead exhibits tumor
regression upon oral dosing in BRAF mutant xenograft models, providing
a promising basis for further optimization toward clinical pERK1/2
modulating ERK1/2 inhibitors
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2
Aberrant activation of the MAPK pathway
drives cell proliferation
in multiple cancers. Inhibitors of BRAF and MEK kinases are approved
for the treatment of BRAF mutant melanoma, but resistance frequently
emerges, often mediated by increased signaling through ERK1/2. Here,
we describe the fragment-based generation of ERK1/2 inhibitors that
block catalytic phosphorylation of downstream substrates such as RSK
but also modulate phosphorylation of ERK1/2 by MEK without directly
inhibiting MEK. X-ray crystallographic and biophysical fragment screening
followed by structure-guided optimization and growth from the hinge
into a pocket proximal to the C-Îą helix afforded highly potent
ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant
cells, the lead compound suppresses pRSK and pERK levels and inhibits
proliferation at low nanomolar concentrations. The lead exhibits tumor
regression upon oral dosing in BRAF mutant xenograft models, providing
a promising basis for further optimization toward clinical pERK1/2
modulating ERK1/2 inhibitors