Total synthesis of the proposed structure of (±)-nidemone has been accomplished either from 2-hydroxy-6-methoxybenzaldehyde (7) or 2-bromo-6-methoxybenzaldehyde (8) in 10 and 13 synthetic steps, respectively. Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in the synthesis.
The A-type Aurora
kinase is upregulated in many human cancers,
and it stabilizes MYC-family oncoproteins, which have long been considered
an undruggable target. Here, we describe the design and synthesis
of a series of pyrimidine-based derivatives able to inhibit Aurora
A kinase activity and reduce levels of cMYC and MYCN. Through structure-based
drug design of a small molecule that induces the DFG-out conformation
of Aurora A kinase, lead compound
13
was identified,
which potently (IC
50
< 200 nM) inhibited the proliferation
of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic
optimization of
13
by prodrug strategies resulted in
orally bioavailable
25
, which demonstrated an 8-fold
higher oral AUC (
F
= 62.3%). Pharmacodynamic studies
of
25
showed it to effectively reduce cMYC protein levels,
leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors
in mice. These results support the potential of
25
for
the treatment of
MYC
-amplified cancers including
SCLC.
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