To satisfy the mitotic checkpoint and drive chromosome congression, the Mps1 kinase lets go of kinetochores by phosphorylating itself in trans (see also related papers by Maciejowski et al. and Santaguida et al. in this issue).
The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.
The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a
key role in DNA replication and repair and may be of interest as an oncology
target. We present the first crystal structure of inhibitor-bound hFEN1 and show
a cyclic N-hydroxyurea bound in the active site coordinated to
two magnesium ions. Three such compounds had similar IC50 values but
differed subtly in mode of action. One had comparable affinity for protein and
protein–substrate complex and prevented reaction by binding to active
site catalytic metal ions, blocking the unpairing of substrate DNA necessary for
reaction. Other compounds were more competitive with substrate. Cellular thermal
shift data showed engagement of both inhibitor types with hFEN1 in cells with
activation of the DNA damage response evident upon treatment. However, cellular
EC50s were significantly higher than in vitro
inhibition constants and the implications of this for exploitation of hFEN1 as a
drug target are discussed.
The RAS/MAPK pathway is a major driver of oncogenesis
and is dysregulated
in approximately 30% of human cancers, primarily by mutations in the
BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1
and ERK2) serve as central nodes within this pathway. The feasibility
of targeting the RAS/MAPK pathway has been demonstrated by the clinical
responses observed through the use of BRAF and MEK inhibitors in BRAF
V600E/K metastatic melanoma; however, resistance frequently develops.
Importantly, ERK1/2 inhibition may have clinical utility in overcoming
acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway
reactivation has occurred, such as relapsed BRAF V600E/K melanoma.
We describe our structure-based design approach leading to the discovery
of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as
excellent physicochemical and absorption, distribution, metabolism,
and excretion (ADME) properties and has demonstrated encouraging antitumor
activity in preclinical models.
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