4 research outputs found
Fragment-Based Discovery of 6‑Azaindazoles As Inhibitors of Bacterial DNA Ligase
Herein we describe the application
of fragment-based drug design
to bacterial DNA ligase. X-ray crystallography was used to guide structure-based
optimization of a fragment-screening hit to give novel, nanomolar,
AMP-competitive inhibitors. The lead compound <b>13</b> showed
antibacterial activity across a range of pathogens. Data to demonstrate
mode of action was provided using a strain of <i>S. aureus</i>, engineered to overexpress DNA ligase
Structure of the Epigenetic Oncogene MMSET and Inhibition by <i>N</i>‑Alkyl Sinefungin Derivatives
The members of the NSD subfamily
of lysine methyl transferases
are compelling oncology targets due to the recent characterization
of gain-of-function mutations and translocations in several hematological
cancers. To date, these proteins have proven intractable to small
molecule inhibition. Here, we present initial efforts to identify
inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal
structural methods. On the basis of 2D NMR experiments comparing NSD1
and MMSET structural mobility, we designed an MMSET construct with
five point mutations in the N-terminal helix of its SET domain for
crystallization experiments and elucidated the structure of the mutant
MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal
systems proved resistant to soaking or cocrystallography with inhibitors.
However, use of the close homologue SETD2 as a structural surrogate
supported the design and characterization of <i>N</i>-alkyl
sinefungin derivatives, which showed low micromolar inhibition against
both SETD2 and MMSET
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-α 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-α 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