Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-<i>N</i>-aryl Propanamides as Novel Smoothened (Smo) Antagonists

Liu, Gang; Duan, Xue; Yang, Jun; Wang, Juan; Liu, Xiaohua; Huang, Wenjing; Li, Jie; Long, Ya Qiu; Tan, Wenfu; Zhang, Ao

doi:10.1021/acs.jmedchem.6b01247

Cited by 26 publications

(22 citation statements)

References 61 publications

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“…1a). Functional characterization of TC114 in a cell-based SMO activation assay confirmed the antagonist activity of TC114 on wild type (WT) SMO and reduced inhibition activity on the drug-resistant mutant (D473H)15 (Supplementary Fig. 2a).…”

Section: Resultsmentioning

confidence: 70%

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

Zhang

Zhao

et al. 2017

Nat Commun

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The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.

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Section: Resultsmentioning

confidence: 70%

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

Zhang

Zhao

et al. 2017

Nat Commun

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“…SMO is a member of class F GPCRs that is responsible for transduction of developmental signals of the Hedgehog (Hh) pathway . The HH signaling pathway plays a critical role in a wide range of cancers and has been considered a therapeutic target for cancer therapy. − …”

Section: Class F Allosteric Gpcr–small-molecule Modulator Interactionsmentioning

confidence: 99%

Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions

2018

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G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors that are most frequently targeted by therapeutic drugs. Allosteric modulators bound to GPCRs at allosteric sites provide the potential for differential selectivity and improved safety compared with traditional orthosteric ligands. The recent breakthroughs in GPCR structural biology have made structures of GPCRs from classes A, B, C, and F complexed with small-molecule allosteric modulators available. Knowledge of the detailed receptor-modulator interactions at the allosteric sites is useful for structure-based GPCR drug design of novel therapeutics. This Perspective comprehensively summarizes the current status of structural complexes between GPCRs and their small-molecule allosteric modulators, particularly the key receptor-modulator interactions at the allosteric sites. Then, the structural diversity of allosteric sites across four GPCR subfamilies is compared. This study is expected to contribute to the design of GPCR allosteric drugs with an improved therapeutic action.

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“…The molecule targets SMO receptor on the same binding site of cyclopamine. Compound 65 showed a good plasma exposure and an acceptable oral bioavailability, and antiproliferative effects in primary Ptch ± ; p53 −/-MB cells both in vitro and in vivo [108].…”

Section: Smo Antagonists Derived From Natural Sourcesmentioning

confidence: 97%

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

Severini

Ghirga

Bufalieri

et al. 2020

Expert Opinion on Therapeutic Targets

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Introduction: Medulloblastoma (MB) is a heterogeneous tumor of the cerebellum that is divided into four main subgroups with distinct molecular and clinical features. Sonic Hedgehog MB (SHH-MB) is the most genetically understood and occurs predominantly in childhood. Current therapies consist of aggressive and non-targeted multimodal approaches that are often ineffective and cause long-term complications. These problems intensify the need to develop molecularly targeted therapies to improve outcome and reduce treatment-related morbidities. In this scenario, Hedgehog (HH) signaling, a developmental pathway whose deregulation is involved in the pathogenesis of several malignancies, has emerged as an attractive druggable pathway for SHH-MB therapy. Areas covered: This review provides an overview of the advancements in the HH antagonist research field. We place an emphasis on Smoothened (SMO) and glioma-associated oncogene homolog (GLI) inhibitors and immunotherapy approaches that are validated in preclinical SHH-MB models and that have therapeutic potential for MB patients. Literature from Pubmed and data reported on ClinicalTrial. gov up to August 2020 were considered. Expert opinion: Extensive-omics analysis has enhanced our knowledge and has transformed the way that MB is studied and managed. The clinical use of SMO antagonists has yet to be determined, however, future GLI inhibitors and multitargeting approaches are promising.

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Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists

Cited by 26 publications

References 61 publications

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

Small Molecule Allosteric Modulators of G-Protein-Coupled Receptors: Drug–Target Interactions

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

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