Biomedical Engineering Reference
In-Depth Information
FIGURE 18.8
Benzopyranyl inhibitor of osteoclast development.
18.6 NATURAL PRODUCT-INSPIRED SMALL-MOLECULE PROBES
DEVELOPED FROM DOS AND BIOLOGY-ORIENTED SYNTHESIS
Over the past decade, the DOS approach has been extended to the exploration of
specific natural product chemotypes [92]. Examples of probes discovered through
this approach are shown in Table 18.3. Also shown are examples of compounds
developed through biology-oriented synthesis (BIOS), a method of probe discovery
that has emerged in parallel with DOS for exploring the chemical space around natural
product hubs.
18.6.1 Activator of the Wnt Pathway Derived from BIOS
The Wnt signaling pathways plays an important role in tissue regeneration and can-
cer [104]. In the canonical Wnt pathway, the cytoplasmic level of
-catenin is kept
low in the absence of Wnt ligand stimulation, as a consequence of
-catenin's phos-
phorylation by glycogen synthase kinase-3
), subsequent ubiquitination
by the Axin complex, and degradation in the proteasome [105]. Activation of the
canonical Wnt pathway inhibits GSK-3
(GSK-3
and stabilizes
-catenin in the cytoplasm.
After translocating to the nucleus,
-catenin binds to the transcription factors that
stimulate transcription of the downstream Wnt genes. The canonical Wnt pathway
