12 research outputs found
The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells
The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6-60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds
The Phosphoinositide-Specific Phospholipase C Inhibitor U73122 (1-(6-((17ÎČ-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) Spontaneously Forms Conjugates with Common Components of Cell Culture Medium
Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP
Inhibitor
of apoptosis proteins (IAPs) are important regulators
of apoptosis and pro-survival signaling pathways whose deregulation
is often associated with tumor genesis and tumor growth. IAPs have
been proposed as targets for anticancer therapy, and a number of peptidomimetic
IAP antagonists have entered clinical trials. Using our fragment-based
screening approach, we identified nonpeptidic fragments binding with
millimolar affinities to both cellular inhibitor of apoptosis protein
1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). Structure-based
hit optimization together with an analysis of proteinâligand
electrostatic potential complementarity allowed us to significantly
increase binding affinity of the starting hits. Subsequent optimization
gave a potent nonalanine IAP antagonist structurally distinct from
all IAP antagonists previously reported. The lead compound had activity
in cell-based assays and in a mouse xenograft efficacy model and represents
a highly promising start point for further optimization
Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and XâLinked Inhibitor of Apoptosis Protein (XIAP)
XIAP and cIAP1 are
members of the inhibitor of apoptosis protein
(IAP) family and are key regulators of anti-apoptotic and pro-survival
signaling pathways. Overexpression of IAPs occurs in various cancers
and has been associated with tumor progression and resistance to treatment.
Structure-based drug design (SBDD) guided by structural information
from X-ray crystallography, computational studies, and NMR solution
conformational analysis was successfully applied to a fragment-derived
lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist
of XIAP and cIAP1 and a structurally novel chemical probe for IAP
biology
A Fragment-Derived Clinical Candidate for Antagonism of XâLinked and Cellular Inhibitor of Apoptosis Proteins: 1â(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethylâ1<i>H</i>,2<i>H</i>,3<i>H</i>âpyrrolo[3,2â<i>b</i>]pyridin-1-yl)-2-[(2<i>R</i>,5<i>R</i>)â5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)
Inhibitor of apoptosis
proteins (IAPs) are promising anticancer
targets, given their roles in the evasion of apoptosis. Several peptidomimetic
IAP antagonists, with inherent selectivity for cellular IAP (cIAP)
over X-linked IAP (XIAP), have been tested in the clinic. A fragment
screening approach followed by structure-based optimization has previously
been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist
lead molecule with a more balanced cIAPâXIAP profile. We now
report the further structure-guided optimization of the lead, with
a view to improving the metabolic stability and cardiac safety profile,
to give the nonpeptidomimetic antagonist clinical candidate <b>27</b> (ASTX660), currently being tested in a phase 1/2 clinical
trial (NCT02503423)
A Fragment-Derived Clinical Candidate for Antagonism of XâLinked and Cellular Inhibitor of Apoptosis Proteins: 1â(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethylâ1<i>H</i>,2<i>H</i>,3<i>H</i>âpyrrolo[3,2â<i>b</i>]pyridin-1-yl)-2-[(2<i>R</i>,5<i>R</i>)â5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)
Inhibitor of apoptosis
proteins (IAPs) are promising anticancer
targets, given their roles in the evasion of apoptosis. Several peptidomimetic
IAP antagonists, with inherent selectivity for cellular IAP (cIAP)
over X-linked IAP (XIAP), have been tested in the clinic. A fragment
screening approach followed by structure-based optimization has previously
been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist
lead molecule with a more balanced cIAPâXIAP profile. We now
report the further structure-guided optimization of the lead, with
a view to improving the metabolic stability and cardiac safety profile,
to give the nonpeptidomimetic antagonist clinical candidate <b>27</b> (ASTX660), currently being tested in a phase 1/2 clinical
trial (NCT02503423)
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 ProteinâProtein Interaction
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