6 research outputs found
A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells
The KRAS oncogene is found in up to 30% of all human
tumors. In
2009, RNAi experiments revealed that lowering mRNA levels of a transcript
encoding the serine/threonine kinase STK33 was selectively toxic to
KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors
of STK33 might selectively target KRAS-dependent cancers. To test
this hypothesis, we initiated a high-throughput screen using compounds
in the Molecular Libraries Small Molecule Repository (MLSMR). Several
hits were identified, and one of these, a quinoxalinone derivative,
was optimized. Extensive SAR studies were performed and led to the
chemical probe ML281 that showed low nanomolar inhibition of purified
recombinant STK33 and a distinct selectivity profile as compared to
other STK33 inhibitors that were reported in the course of these studies.
Even at the highest concentration tested (10 μM), ML281 had
no effect on the viability of KRAS-dependent cancer cells. These results
are consistent with other recent reports using small-molecule STK33
inhibitors. Small molecules having different chemical structures and
kinase-selectivity profiles are needed to fully understand the role
of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable
addition to small-molecule probes of STK33
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>‑Glycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>‑Glycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>‑Glycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria
Here, we describe the discovery of a novel antimalarial
agent using phenotypic screening of <i>Plasmodium falciparum</i> asexual blood-stage parasites. Screening a novel compound collection
created using diversity-oriented synthesis (DOS) led to the initial
hit. Structure–activity relationships guided the synthesis
of compounds having improved potency and water solubility, yielding
a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized
compound <b>27</b> has an excellent off-target activity profile
in erythrocyte lysis and HepG2 assays and is stable in human plasma.
This compound is available via the molecular libraries probe production
centers network (MLPCN) and is designated ML238
Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects
The
mood stabilizer lithium, the first-line treatment for bipolar
disorder, is hypothesized to exert its effects through direct inhibition
of glycogen synthase kinase 3 (GSK3) and indirectly by increasing
GSK3’s inhibitory serine phosphorylation. GSK3 comprises two
highly similar paralogs, GSK3α and GSK3β, which are key
regulatory kinases in the canonical Wnt pathway. GSK3 stands as a
nodal target within this pathway and is an attractive therapeutic
target for multiple indications. Despite being an active field of
research for the past 20 years, many GSK3 inhibitors demonstrate either
poor to moderate selectivity versus the broader human kinome or physicochemical
properties unsuitable for use in <i>in vitro</i> systems
or <i>in vivo</i> models. A nonconventional analysis of
data from a GSK3β inhibitor high-throughput screening campaign,
which excluded known GSK3 inhibitor chemotypes, led to the discovery
of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled
kinome-wide selectivity for the GSK3 kinases. Taking advantage of
an uncommon tridentate interaction with the hinge region of GSK3,
we developed highly selective and potent GSK3 inhibitors, <b>BRD1652</b> and <b>BRD0209</b>, which demonstrated <i>in vivo</i> efficacy in a dopaminergic signaling paradigm modeling mood-related
disorders. These new chemical probes open the way for exclusive analyses
of the function of GSK3 kinases in multiple signaling pathways involved
in many prevalent disorders