Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

Manetti, Fabrizio; Taddei, Maurizio; Petricci, Elena

doi:10.1007/7355_2014_61

Cited by 6 publications

(3 citation statements)

References 127 publications

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“…In recent years, drug discovery efforts directed against the Hh pathway have been focused predominantly on the development of SMO antagonists and a remarkable number of small molecules of natural, semisynthetic or synthetic origin have been developed and extensively reviewed in recent reports [23][24][25]. Several SMO antagonists have demonstrated efficacy in mouse xenografts and, most notably, have been investigated in clinical trials against a large range of metastatic and advanced cancers [26,27].…”

Section: Smo Antagonists: Pitfalls and Limitationsmentioning

confidence: 99%

Targeting GLI factors to inhibit the Hedgehog pathway

Infante

Alfonsi

Botta

et al. 2015

Trends in Pharmacological Sciences

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Hedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathway activation or the occurrence of drug-resistant SMO mutations. Recently, particular interest has been elicited by the identification of molecules able to hit glioma-associated oncogene (GLI) factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-SMO resistance. Here, we review results achieved in developing GLI antagonists, explaining their mechanisms of action and highlighting their therapeutic potential. We also underline the relevance of structural details in their discovery and optimization.

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Section: Smo Antagonists: Pitfalls and Limitationsmentioning

confidence: 99%

Targeting GLI factors to inhibit the Hedgehog pathway

Infante

Alfonsi

Botta

et al. 2015

Trends in Pharmacological Sciences

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“…Significantly decreased levels of phospho-PFKFB3 have been found upon treatment with the MK2 inhibitor 30 , thus demonstrating a direct involvement of MK2 in the phosphorylation and activation of PFKFB3. 55 This very intriguing result suggested that the combined administration of MK2 inhibitors and small molecules able to block the Hh pathway 56-59 could be a useful strategy for the treatment of specific tumors, such as the breast cancer.…”

Section: Crystallization Studiesmentioning

confidence: 99%

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

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The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway, but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases, to prevent tumor metastasis, and to increase tumor sensitivity to chemotherapeutics.

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“…In adults, the Hh pathway remains active and is involved in regulation of tissue homeostasis, continuous renewal and repair of adult tissues, and stem cell maintenance [6]. Hh signaling pathway is controlled by membrane proteins Patched (Ptch) and Smoothened (Smo), the signal transducer (the effector component), transmembrane receptors (Ptch1-2), downstream regulators (SuFu) and as well as transcription factors (Gli1-3) [7]. When there is no ligand bound to Ptch, Ptch inhibits Smo and keeps the downstream pathway inactivated (Figure: 1) When Hh ligand binds to Ptch, the inhibition of Ptch on Smo is relieved and the Hh-signaling pathway is activated.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of hedgehog signaling pathway agonist

Poonam¹,

Sharma²,

Shivali³

et al. 2019

World J. Adv. Res. Rev.

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The Hedgehog (Hh) signaling pathway plays an important role in the growth, development, and homeostasis of many tissues in vertebrates and invertebrates in embryonic stage. However, Hh signaling is also involved in postnatal processes such as tissue repair and adult immune responses. To some extent, Hh signaling has also been shown to be a target for some pathogens like HIV, EVB and influenza that presumably utilize the pathway to control the local infected environment. In present review, we discuss the detailed mechanism of the Hedgehog (Hh) signaling pathway involved in various disease being a target. We also give a range of agonist and on the possibility of using small molecule modulators of Hh signaling as effective therapies for a wider range of human diseases.

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Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

Cited by 6 publications

References 127 publications

Targeting GLI factors to inhibit the Hedgehog pathway

Targeting GLI factors to inhibit the Hedgehog pathway

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

Therapeutic potential of hedgehog signaling pathway agonist

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