result of the team’s drug design strategy
was MK-7009, a potent and selective inhibitor of HCV NS3/4A protease. The team
determined that the compound efficiently
reached its site of action, liver tissue, in
preclinical animal studies. MK-7009 is administered orally and is currently in Phase
I clinical trials.
relapse where androgen ablation
therapy no longer staves off the
cancer.
The latest research in this area
has found that such relapses are
directly related to reactivation of
the AR signaling pathway in tumor
cells. Through pathways that reactivate AR, prostate cancer cells
find a way to grow despite the reduced androgen levels created by
androgen ablation therapy. Therefore, Salvati noted, using highly potent androgen
receptor antagonists that more completely
block the AR signaling pathway might be
a better treatment
option for advanced
prostate cancer than
O the currently avail-
O able therapies.
N O The BMS team
applied structure-
H HN S based drug design
H O and medicinal
chemistry ap-
proaches to de-
velop BMS-641988.
They began by analyzing how a known
AR blocker interacted with its target and
made modifications to increase potency
and generate new antagonists that bind
differently to the AR compared with exist-
ing antagonists. Such antagonists may
FOLLOWING McCauley’s talk, Mark E.
Salvati, associate director of discovery oncology chemistry at Bristol-Myers Squibb
(BMS), in Princeton, N. J., disclosed the
structure of BMS-641988, a drug candidate
for the treatment of advanced prostate
cancer. BMS-641988
is an antagonist CF (blocking agent)
3
associated with the NC
androgen receptor
(AR), which modulates gene expression in response O
to those male hormones that promote
the growth of prostate tumors. Salvati
suggested that BMS-641988 may give new
hope to patients with advanced prostate
cancer because it emerged from research
that answered some questions about why
established prostate cancer treatments
ultimately fail.
Currently, patients with prostate cancer
may be given chemical or surgical castration treatment along with an AR antagonist, a therapy referred to as androgen
ablation. This therapy seeks to deprive
the body of androgens and yields about 18
months of disease remission. However,
nearly all of these patients experience a
CHARLOTTE RAYMOND/BMS
circumvent many of
the pathways leading
to androgen ablation
relapse, Salvati told
C&EN. The efforts of
his team culminated
in BMS-641988, a
highly potent and
selective AR antagonist. In preclinical
tests, BMS-641988
effectively blocked
the growth of an in
vivo human prostate tumor model
made resistant to
continued bicalutamide treatment.
Bicalutamide is the
gold standard AR antagonist. In addition,
the team showed
at the genomic and
proteomic levels that
BMS-641988 better
blocked the AR signaling pathway compared with bicalutamide. BMS-641988
is given to patients
orally and is currently in Phase I clinical
trials for the treatment of prostate cancer.
CANCER GROUP Key
BMS personnel behind
BMS-641988 are (from
left) Stanley R. Krystek,
Mary Obermeier, Marco M.
Gottardis, George L. Trainor,
Ricardo M. Attar, Salvati,
Aaron J. Balog, Shinta
Cheng, Gregory D. Vite, and
Maria N. Jure-Kunkel.
BMS-641988
THE THIRD SPEAKER was Bradley R.
Teegarden, associate director of medicinal
chemistry at Arena Pharmaceuticals in San
Diego. He described his team’s discovery
of APD791, a drug candidate that interferes
with blood clot formation.
Clotting is essential to prevent excessive blood loss after injury. But when blood
vessels are obstructed and blood flow is
restricted, clotting can also lead to heart
attack or stroke. Many patients receive clot-reducing therapy to lower the risk of strokes
or heart attacks. Such treatments include
aspirin and clopidogrel, which is marketed
under the brand name Plavix by BMS and
Sanofi-Aventis. But these drugs prevent
clotting so well that they can lead to excessive bleeding after an injury, Teegarden said.
Clots are an aggregate of specialized cells
As a drug becomes more successful,
people typically hear more about the
drug itself and less about the arduous
process that went into its discovery.
