Synthetic Small Molecule Inhibitors of Hh Signaling As Anti-Cancer Chemotherapeutics

Abstract

The hedgehog (Hh) pathway is a developmental signaling pathway that is essential to the proper embryonic development of many vertebrate systems. Dysregulation of Hh signaling has been implicated as a causative factor in the development and progression of several forms of human cancer. As such, the development of small molecule inhibitors of Hh signaling as potential anti-cancer chemotherapeutics has been a major area of research interest in both academics and industry over the past ten years. Through these efforts, synthetic small molecules that target multiple components of the Hh pathway have been identified and advanced to preclinical or clinical development. The goal of this review is to provide an update on the current status of several synthetic small molecule Hh pathway inhibitors and explore the potential of several recently disclosed inhibitory scaffolds.

Fig. (1)

The Hh signaling cascade in the absence (A) or presence (B) of Hh ligand.

Fig. (2)

Structures of established Smo antagonists.

Fig. (3)

Recently characterized Smo antagonists.

Fig. (4)

Structures of azole anti-fungals that inhibit Hh signaling.

Fig. (5)

Hh Pathway inhibitors that disrupt Smo ciliary distribution.

Fig. (6)

Benzamide-based Smo antagonists.

Fig. (7)

Additional vismodegib-based Smo antagonists.

Fig. (8)

Sterol-based smo antagonists.

Fig. (9)

Additional Smo modulators utilized for structural studies.

Fig. (10)

Hh pathway inhibitors that function upstream of Smo in the signaling cascade.

Fig. (11)

Pathway inhibitors that function at the level of Gli.

Fig. (12)

Hh inhibitors with indirect actions on pathway signaling.

Fig. (13)

Small molecule pathway inhibitors that function through an undetermined mechanism.