3 research outputs found
A Selective and Slowly Reversible Inhibitor of l‑Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells
The l-type
amino acid transporter 1 (LAT1) is a transmembrane
protein carrying bulky and neutral amino acids into cells. LAT1 is
overexpressed in several types of tumors, and its inhibition can result
in reduced cancer cell growth. However, known LAT1 inhibitors lack
selectivity over other transporters. In the present study, we designed
and synthesized a novel selective LAT1 inhibitor (<b>1</b>),
which inhibited the uptake of LAT1 substrate, l-leucin as
well as cell growth. It also significantly potentiated the efficacy
of bestatin and cisplatin even at low concentrations (25 μM).
Inhibition was slowly reversible, as the inhibitor was able to be
detached from the cell surface and blood–brain barrier. Moreover,
the inhibitor was metabolically stable and selective toward LAT1.
Since the inhibitor was readily accumulated into the prostate after
intraperitoneal injection to the healthy mice, this compound may be
a promising agent or adjuvant especially for the treatment of prostate
cancer
A Selective and Slowly Reversible Inhibitor of l‑Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells
The l-type
amino acid transporter 1 (LAT1) is a transmembrane
protein carrying bulky and neutral amino acids into cells. LAT1 is
overexpressed in several types of tumors, and its inhibition can result
in reduced cancer cell growth. However, known LAT1 inhibitors lack
selectivity over other transporters. In the present study, we designed
and synthesized a novel selective LAT1 inhibitor (<b>1</b>),
which inhibited the uptake of LAT1 substrate, l-leucin as
well as cell growth. It also significantly potentiated the efficacy
of bestatin and cisplatin even at low concentrations (25 μM).
Inhibition was slowly reversible, as the inhibitor was able to be
detached from the cell surface and blood–brain barrier. Moreover,
the inhibitor was metabolically stable and selective toward LAT1.
Since the inhibitor was readily accumulated into the prostate after
intraperitoneal injection to the healthy mice, this compound may be
a promising agent or adjuvant especially for the treatment of prostate
cancer
Exploration of a Series of 5‑Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin
A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones
were
investigated as inhibitors of the lymphocyte-expressed pore-forming
protein perforin. Structure–activity relationships were explored
through variation of an isoindolinone or 3,4-dihydroisoquinolinone
subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The
ability of the resulting compounds to inhibit the lytic activity of
both isolated perforin protein and perforin delivered in situ by natural
killer cells was determined. A number of compounds showed excellent
activity at concentrations that were nontoxic to the killer cells,
and several were a significant improvement on previous classes of
inhibitors, being substantially more potent and soluble. Representative
examples showed rapid and reversible binding to immobilized mouse
perforin at low concentrations (≤2.5 μM) by surface plasmon
resonance and prevented formation of perforin pores in target cells
despite effective target cell engagement, as determined by calcium
influx studies. Mouse PK studies of two analogues showed <i>T</i><sub>1/2</sub> values of 1.1–1.2 h (dose of 5 mg/kg iv) and
MTDs of 60–80 mg/kg (ip)