Recent patents for Hedgehog pathway inhibitors for the treatment of malignancy

Abstract

Background: There is increasing evidence suggesting that blocking aberrant Hedgehog (Hh) signaling can be a novel therapeutic avenue for the treatment of cancer. During the past decade, efforts from academic and industrial groups have led to the discovery of a variety of Hh pathway inhibitors. Objective: This review covers the patent literature related to Hh pathway inhibitors for the treatment of proliferative diseases, regardless of their modes of action. Methods: A comprehensive survey of the patent literature since 1999 is presented. Results/conclusion: Most reported Hh pathway inhibitors act on the key signaling transducer Smoothened (SMO). Screening of compound libraries using reporter and binding assays have identified a broad diversity of chemical structures that interact with SMO. These screening approaches, followed by conventional medicinal chemistry, have delivered important clinical drug candidates, such as GDC-0449 and XL-139. In addition, modification of the naturally occurring Veratrum alkaloid cyclopamine has resulted in various active analogues, including clinical drug candidate IPI-926. Although there are recent scientific literature reports of small molecules acting downstream of SMO, there is limited patent literature on this mode of Hh pathway inhibition.

Keywords::

• anticancer
• basal cell carcinoma
• cyclopamine
• GDC-0449
• GLI
• hedgehog
• IPI-926
• medulloblastoma
• natural product
• Patched
• Smoothened
• XL-139

Acknowledgments

The authors thank Karen McGovern and Margaret A. Read for discussions during the preparation of the manuscript. The authors also thank Dianne Barry, consultant in medical communication, for assistance in writing the manuscript. We sincerely apologize for any omissions; the task of summarizing the many exciting recent developments in this field was enormous.