Sunday, January 17, 2016

Vismodegib I Hedgehog Pathway Inhibitor | Basal Cell Carcinoma Therapy | Cancer Drug

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 provides a treatment option for patients with locally advanced or metastatic BCC for whom surgery or radiation is not recommended.


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

WO2009126863A2: also see Ref. 1. It all started from here.


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).

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.

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