Targeted
protein degradation using chimeric small molecules such
as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic
inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs)
is an emerging modality in drug discovery. Here, we expand the repertoire
of E3 ligases capable of ubiquitylating target proteins using this
system. By incorporating β-naphthoflavone (β-NF) as a
ligand, we developed a novel class of chimeric molecules that recruit
the arylhydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA,
a chimeric degrader directed against cellular retinoic acid binding
proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1
and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound
ITE-ATRA, in which an alternative AhR ligand was used, also degraded
CRABP proteins. Finally, we developed a chimeric compound β-NF-JQ1
that is directed against bromodomain-containing (BRD) proteins using
β-NF as an AhR ligand. β-NF-JQ1 induced the interaction
of AhR and BRD proteins and displayed effective anticancer activity
that correlated with protein knockdown activity. These results demonstrate
a novel class of chimeric degrader molecules based on the ability
to bring a target protein and an AhR E3 ligase into close proximity.
Duplex DNA adopts a right-handed B-DNA conformation under physiological conditions. Z-DNA, meanwhile, has a left-handed helical structure and is in equilibrium with right-handed B-DNA. We recently reported that the bisnaphthyl maleimide-spermine conjugate (1) induced a B- to Z-DNA transition with high efficiency at low salt concentrations. It was also found that the bisnaphthyl ligand (1) spontaneously transformed into the corresponding [5]helicene derivative (2). Because [5]helicene 2 can potentially be chiral and because the chiral discrimination of B- and Z-DNA is also of interest, we became interested in whether enatiomerically pure [5]helicene-spermine conjugates might discriminate the chirality of B- or Z-DNA. In this study, we have demonstrated an efficient synthesis of chiral DNA-binding ligands by the conjugation of a [5]helicene unit with a spermine unit. These chiral helicene ligands exhibited recognition of B- and Z-DNA, with (P)-3 displaying preference for B-DNA and (M)-3 for Z-DNA. The characteristic features of the helicene-spermine ligands developed in this study include two points: the cationic spermine portion produces electrostatic interactions along the phosphate backbone of the minor groove, and the helicene forms complexes in an end-stacking mode. Such binding modes, together with the thermodynamic parameters, account for the mode of chiral recognition of (P)- and (M)-3 for B- and Z-DNA.
Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations.
Targeted protein degradation using
chimeric small molecules, such
as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic
inhibitors of apoptosis protein (IAP)-dependent protein erasers (SNIPERs),
has attracted attention as a method for degrading intracellular target
proteins via the ubiquitin-proteasome system (UPS). These chimeric
molecules target a variety of proteins using small molecules that
can bind to the proteins. However, it is difficult to develop such
degraders in the absence of suitable small-molecule ligands for the
target proteins, such as for transcription factors (TFs). Therefore,
we constructed the chimeric molecule LCL-ER(dec), which
consists of a decoy oligonucleotide that can bind to estrogen receptor
α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) was found to selectively degrade ERα via
the UPS. These findings will be applicable to the development of other
oligonucleotide-type degraders that target different TFs.
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