Hedgehog signaling pathway inhibitors: an updated patent review (2015–present)

ABSTRACT

Introduction: Hedgehog (Hh) signaling plays a pivotal role in tissue development and stemness, and its deregulation is found in many different tumors. Several efforts have been devoted to discovery of Hh inhibitors, including three drugs approved by the Food and Drug Administration (FDA), targeting the upstream receptor smoothened (SMO). However, SMO mutations or SMO-independent Hh pathway activation raise the need for novel Hh inhibitors.

Areas covered: This review describes Hh inhibitors with anticancer potential patented in the period 2015–present.

Expert opinion: Despite the initial enthusiasm in SMO antagonists, drug-resistant mutations, and SMO-independent Hh activation limited their clinical application. A growing number of therapeutic strategies are currently focusing on downstream Hh effectors (i.e. glioma-associate oncogenes (GLI) proteins) or other signaling pathways related to Hh, in addition to drug repositioning. Given the heterogenic nature of cancers, a terrific clinical impact is expected by multi-targeting approaches able to modulate simultaneously SMO and GLI, and/or additional targets that act as regulators of Hh signaling. It is expected that these alternative strategies might be investigated in clinical trials in the next years against a wide variety of tumor types, and that they provide improved outcomes compared to current SMO antagonists or other single-agent anticancer drugs.

KEYWORDS:

• Cancer
• drug discovery
• GLI
• Hedgehog
• multi-target
• signaling pathway
• small molecules
• SMO

Article highlights

• Targeting the Hedgehog signaling pathway is a promising and very active field in anticancer drug discovery.

• Antagonists of the Smoothened receptor experienced clinical failure mostly because of drug-resistant mutations or pathway activation downstream of Smoothened.

• Targeting the resistant forms of Smoothened and/or the downstream effectors GLI represent the main strategies to overcome drug resistance.

• GLI inhibitors proved highly effective, although they are still at the preclinical stage of development.

• The development of multitarget Hedgehog inhibitors emerged as a highly promising approach that might be strongly developed in next years.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Fondazione AIRC per la ricerca sul Cancro Grant #IG20801 to L.D.M., Progetti di Ricerca di Università Sapienza di Roma, Italian Ministry of Health Grant PRIN 2017 to L.D.M., Dipartimenti di Eccellenza - L. 232/2016, Pasteur Institute/Cenci Bolognetti Foundation, Istituto Italiano di Tecnologia (IIT).