Hedgehog pathway inhibitors

Hedgehog pathway inhibitors are a class of drugs being developed for treatment of cancer. The hedgehog signaling pathway is involved in cancer development, and as such is the target of efforts for many types of cancers.

Most of these compounds affect the hedgehog signaling pathway via inhibition of smoothened (Smo), a key component of the pathway. Depending on when a Hh inhibiting compound is approved by the U.S. Food and Drug Administration (FDA), there may be a perceived need for one to be differentiated over another for marketing purposes, which could lead to different nomenclature (e.g., a Hhi or an agonist of Smo). This marketing technique is more of a differentiation strategy than a scientific property of these compounds, as the mechanism of action (MOA) in the end is inhibition of the Hh pathway, targeting cancer stem cells. However, as these new compounds are further studied, identification of differences in a compound's MOA, could lead to hypotheses regarding the stage at which Smo is inhibited, where along the pathway the compound binds, or specific binding properties of a compound. If these hypotheses are proven, claims could be made regarding a specific compound's MOA and how it affects efficacy, safety, combinability with other cancer treatments, etc. Scientific data in support of such hypotheses have not been published to date.

There are several Hh inhibitors recently approved or in clinical development. The first, vismodegib, was FDA-approved in 2012, for treating basal cell carcinoma. Sonidegib was approved in 2015 for the same indication.

Itraconazole is an anti-fungal drug that has been shown to inhibit hedgehog signaling and has been preliminarily studies for use in cancer.

Other compounds in the class include:^[1]

• Exelixis/Bristol-Myers Squibb's BMS-833923
• Millennium Pharmaceuticals's TAK-441
• Pfizer's PF-04449913 (Glasdegib)

References