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.

Hedgehog signaling pathway inhibitors: an updated patent review (2015–present) / Quaglio, D.; Infante, P.; Di Marcotullio, L.; Botta, B.; Mori, M.. - In: EXPERT OPINION ON THERAPEUTIC PATENTS. - ISSN 1354-3776. - 30:4(2020), pp. 235-250. [10.1080/13543776.2020.1730327]

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

Quaglio D.;Infante P.;Di Marcotullio L.;Botta B.;
2020

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.
2020
Cancer; drug discovery; GLI; Hedgehog; multi-target; signaling pathway; small molecules; SMO
01 Pubblicazione su rivista::01g Articolo di rassegna (Review)
Hedgehog signaling pathway inhibitors: an updated patent review (2015–present) / Quaglio, D.; Infante, P.; Di Marcotullio, L.; Botta, B.; Mori, M.. - In: EXPERT OPINION ON THERAPEUTIC PATENTS. - ISSN 1354-3776. - 30:4(2020), pp. 235-250. [10.1080/13543776.2020.1730327]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1384485
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