6 research outputs found
Discovery of Potent KIFC1 Inhibitors Using a Method of Integrated High-Throughput Synthesis and Screening
KIFC1
(HSET), a member of the kinesin-14 family of motor proteins,
plays an essential role in centrosomal bundling in cancer cells, but
its function is not required for normal diploid cell division. To
explore the potential of KIFC1 as a therapeutic target for human cancers,
a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold
was developed from hits identified through high-throughput screening
(HTS). Optimization of the initial hits combined both designâsynthesisâtest
cycles and an integrated high-throughput synthesis and biochemical
screening method. An important aspect of this integrated method was
the utilization of DMSO stock solutions of compounds registered in
the corporate compound collection as synthetic reactants. Using this
method, over 1500 compounds selected for structural diversity were
quickly assembled in assay-ready 384-well plates and were directly
tested after the necessary dilutions. Our efforts led to the discovery
of a potent KIFC1 inhibitor, <b>AZ82</b>, which demonstrated
the desired centrosome declustering mode of action in cell studies
Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1âPhosphate Receptor 1 Antagonists with in Vivo Activity
We
report here a novel series of benzimidazole sulfonamides that
act as antagonists of the S1P<sub>1</sub> receptor, identified by
exploiting an understanding of the pharmacophore of a high throughput
screening (HTS)-derived series of compounds described previously.
Lead compound <b>2</b> potently inhibits S1P-induced receptor
internalization in a cell-based assay (EC<sub>50</sub> = 0.05 ÎŒM),
but has poor physical properties and metabolic stability. Evolution
of this compound through structureâactivity relationship development
and property optimization led to <i>in vivo</i> probes such
as <b>4</b>. However, this compound was unexpectedly found to
be a potent CYP3A inducer in human hepatocytes, and thus further chemistry
efforts were directed at addressing this liability. By employing a
pregnane X receptor (PXR) reporter gene assay to prioritize compounds
for further testing in human hepatocytes, we identified lipophilicity
as a key molecular property influencing the likelihood of P450 induction.
Ultimately, we have identified compounds such as <b>46</b> and <b>47</b>, which demonstrate the desired S1P<sub>1</sub> antagonist
activity while having greatly reduced risk of CYP3A induction in humans.
These compounds have excellent oral bioavailability in preclinical
species and exhibit pharmacodynamic effects of S1P<sub>1</sub> antagonism
in several <i>in vivo</i> models following oral dosing.
Relatively modest antitumor activity was observed in multiple xenograft
models, however, suggesting that selective S1P<sub>1</sub> antagonists
would have limited utility as anticancer therapeutics as single agents
Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1âPhosphate Receptor 1 Antagonists with in Vivo Activity
We
report here a novel series of benzimidazole sulfonamides that
act as antagonists of the S1P<sub>1</sub> receptor, identified by
exploiting an understanding of the pharmacophore of a high throughput
screening (HTS)-derived series of compounds described previously.
Lead compound <b>2</b> potently inhibits S1P-induced receptor
internalization in a cell-based assay (EC<sub>50</sub> = 0.05 ÎŒM),
but has poor physical properties and metabolic stability. Evolution
of this compound through structureâactivity relationship development
and property optimization led to <i>in vivo</i> probes such
as <b>4</b>. However, this compound was unexpectedly found to
be a potent CYP3A inducer in human hepatocytes, and thus further chemistry
efforts were directed at addressing this liability. By employing a
pregnane X receptor (PXR) reporter gene assay to prioritize compounds
for further testing in human hepatocytes, we identified lipophilicity
as a key molecular property influencing the likelihood of P450 induction.
Ultimately, we have identified compounds such as <b>46</b> and <b>47</b>, which demonstrate the desired S1P<sub>1</sub> antagonist
activity while having greatly reduced risk of CYP3A induction in humans.
These compounds have excellent oral bioavailability in preclinical
species and exhibit pharmacodynamic effects of S1P<sub>1</sub> antagonism
in several <i>in vivo</i> models following oral dosing.
Relatively modest antitumor activity was observed in multiple xenograft
models, however, suggesting that selective S1P<sub>1</sub> antagonists
would have limited utility as anticancer therapeutics as single agents