Evaluation of WO2014207069 A1: Multitarget Hedgehog pathway inhibitors and uses thereof

ABSTRACT

In recent years, the involvement of the Hedgehog (Hh) signaling pathway in various human diseases and dysfunctions has been clearly demonstrated. Smoothened (Smo), one of the upstream signal transducers, has been the most druggable target of the Hh pathway. However, the emergence of resistance to Smo inhibitors and the identification of Smo-independent activation of the Hh pathway led to the need to find new chemical entities able to interfere with downstream components, such as Gli. For this purpose, two different computational approaches have been applied to a small-sized library of natural compounds. As a result, an isoflavone derivative that showed ability to inhibit both Smo and Gli1 has been identified; namely, Glabrescione B. A new synthetic approach has been planned for this compound and its derivatives. Biological evaluation demonstrated the mechanism of action and showed a promising preclinical profile.

KEYWORDS:

• Gli1 inhibitors
• Hedgehog-dependent cancers
• Hedgehog signaling pathway
• isoflavone
• naturally occurring molecules

Financial and competing interests disclosure

F Manetti is an Associate Professor at the Università di Siena (Italy), which is one of the two applicants for the patent under evaluation (WO2014207069). F Manetti has previously co-authored works with three inventors of this patent. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.