Vismodegib
[2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide]
is the first Hedgehog (Hh) pathway inhibitor approved in the US for the
treatment of adults with metastatic or locally advanced basal cell carcinoma
(BCC). Vismodegib selectively inhibits the Hh signaling pathway, binding to and
inhibiting a critical signal-transducing component of the pathway, Smoothened
(SMO).
 |
| Vismodegib |
Vismodegib
inhibited the luciferase activity (IC50 = 0.013 uM) in HTS screen
based on murine 10T1/2 (S12) embryonic fibroblast cells containing a plasmid
with a luciferase reporter gene downstream of Gli (Hh transcription factor) binding
sites.
It was
approved by the US FDA on 30 January 2012, and by the European Commission on 12
July 2013, for the treatment of adult patients with symptomatic metastatic BCC,
or locally advanced BCC inappropriate for surgery or radiotherapy.
The Hh
pathway has been studied extensively using the natural product cyclopamine, a
steroidal alkaloid that blocks Hh signaling with an EC50 of
approximately 300 nM and has been shown to bind SMO. It modifies Hh pathway
activation in cell cultures, and also inhibits the proliferation of human
medulloblastoma and basal cell carcinoma skin explants. However, its structural
complexity, scarcity, poor aqueous solubility, and poor chemical stability in
acid, limits the use of cyclopamine as a viable therapeutic agent. This ignited
the researchers to identify small molecule Hh antagonists of a different
chemical class.
Researchers
from Genetech, Curis and Evotec, started with a HTS identification of Hh
pathway antagonists and finally ended with a series of 2-pyridyl amides which
has been optimised for potency, pharmacokinetics (PK), and drug-like properties
by modifications to the amide portion of the molecule resulting in Vismodegib
[1].
Hedgehog Pathway and Cancers:
In the
case of the Hedgehog (Hh) pathway, the 12 transmembrane receptor patched (PTCH)
is a negative regulator of the seven transmembrane receptor smoothened (SMO).
PTCH is the receptor for the Hh ligand and inhibits SMO until the Hh ligand
binds, allowing SMO to signal. Through an intracellular pathway that is still
incompletely understood, this signaling event results in the nuclear
translocation of the Hh transcription factors Gli1 and Gli2, which initiate
transcription of Hh responsive genes.
During
development, this pathway is responsible for embryonic patterning in a variety
of tissues.
In
patients afflicted with Gorlin Syndrome, a mutation of the negative regulator,
PTCH, causes uncontrolled SMO signaling producing multiple basal cell
carcinomas (BCC) along with much higher growth rates of other cancers.
There
is also strong evidence linking alterations in the Hh pathway to sporadic BCC, medulloblastoma,
small cell lung, and gastro-intestinal tract cancers, among others [1].
Vismodegib Synthesis
Identification:
 |
| 1H NMR (Estimated) for Vismodegib |
Experimental: 1H NMR
(400MHz, CDCl3) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03
(dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d,
J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).
Sideeffects:
Adverse
events (AEs) occurring in greater than 10% of patients included muscle spasms, arthralgia
(joint pain), alopeica, weight loss, fatigue, nausea, diarrhea, decreased
appetite, constipation, dysgeusia or ageusia (taste disturbance or taste loss) and
vomiting.
References:
1. Robarge,
K. D.; et. al. GDC-0449-a potent
inhibitor of the hedgehog pathway. Bioorg Med Chem Lett 2009, 19(19), 5576-5581.
2. Gunzner, J. L.; et. al. Pyridyl inhibitors of hedgehog signalling. WO2009126863A2
