Recent Development of Non-Peptide GnRH Antagonists

Tukun, Feng-Ling; Olberg, Dag Erlend; Riss, Patrick J.; Haraldsen, Ira; Kaass, Anita; Klaveness, Jo

doi:10.3390/molecules22122188

Cited by 41 publications

(37 citation statements)

References 80 publications

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“…F34 is analogous to Relugolix and Sufugolix, incorporating thieno[2,3-d]pyrimidin-4(3H)-one as a common scaffold. Both of these compounds act as an antagonist for the gonadotropin-releasing hormone, which is being clinically studied for prostate cancer, uterine leiomyoma, and endometriosis [161,162].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

et al. 2019

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Tumorigenesis in humans is a multistep progression that imitates genetic changes leading to cell transformation and malignancy. Oncogenic kinases play a central role in cancer progression, rendering them putative targets for the design of anti-cancer drugs. The presented work aims to identify the potential multi-target inhibitors of oncogenic receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs). For this, chemoinformatics and structure-based virtual screening approaches were combined with an in vitro validation of lead hits on both cancerous and non-cancerous cell lines. A total of 16 different kinase structures were screened against ~739,000 prefiltered compounds using diversity selection, after which the top hits were filtered for promising pharmacokinetic properties. This led to the identification of 12 and 9 compounds against RTKs and STKs, respectively. Molecular dynamics (MD) simulations were carried out to better comprehend the stability of the predicted hit kinase-compound complexes. Two top-ranked compounds against each kinase class were tested in vitro for cytotoxicity, with compound F34 showing the most promising inhibitory activity in HeLa, HepG2, and Vero cell lines with IC50 values of 145.46 μM, 175.48 μM, and 130.52 μM, respectively. Additional docking of F34 against various RTKs was carried out to support potential multi-target inhibition. Together with reliable MD simulations, these results suggest the promising potential of identified multi-target STK and RTK scaffolds for further kinase-specific anti-cancer drug development toward combinatorial therapies.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

et al. 2019

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“…In combination with aromatase inhibitors, GnRH antagonists suppress estrogen levels beyond those achieved alone [193]. Due to the interesting pharmacological profile of GnRHR antagonists, a number of non-peptidic (heterocyclic) molecules sharing various pharmacophores, such as, for example, substituted thieno[2,3- b ]pyridine-4-ones, thieno[2,3- d ]pyrimidin-2,4-diones, pyrrolo[1,2- a ]pyrimidin-7-ones, imidazolo[1,2- a ]pyrimidin-5-ones or uracil derivatives, have been synthesized [199,200,201].…”

Section: Gpcrs In Breast Cancer: Signaling Biology and Modulatorsmentioning

confidence: 99%

GPCR Modulation in Breast Cancer

Lappano

Jacquot

Maggiolini

2018

IJMS

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Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals.

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“…Currently, Elagolix is the only nonpeptidic GnRH‐R antagonist that is marketed, but several others are in development. [ 131 ] Besides that, a large number of small molecule drug conjugates (SMDCs) for targeted tumor therapy has been developed. Virtually all of them address plasma membrane‐associated enzymes, transporter proteins or cell surface receptors that are not peptide receptors.…”

Section: Small Molecules For Targeting Peptide‐binding Receptors On Cmentioning

confidence: 99%

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

2020

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Specifically addressing cell surface molecules on cancer cells facilitates targeted cancer therapies that offer the potential to selectively destroy malignant cells, while sparing healthy tissue. Thus, undesired side-effects in tumor patients are highly reduced. Peptide-binding receptors are frequently overexpressed on cancer cells and therefore promising targets for selective tumor therapy. In this review, peptidebinding receptors for anti-cancer drug delivery are summarized with a focus on peptide ligands as delivery agents. In the first part, some of the most studied peptidebinding receptors are presented, and the ghrelin receptor and the Y 1 receptor are introduced as more recent targets for cancer therapy. Furthermore, nonpeptidic small molecules for receptor targeting on cancer cells are outlined. In the second part, peptide conjugates for the delivery of therapeutic cargos in cancer therapy are described.The essential properties of receptor-targeting peptides are specified, and recent developments in the fields of classical peptide-drug conjugates with toxic agents, radiolabeled peptides for radionuclide therapy, and boronated peptides for boron neutron capture therapy are presented. K E Y W O R D SBNCT, G protein-coupled receptor, internalization, peptide drug conjugate, tumor targeting

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Recent Development of Non-Peptide GnRH Antagonists

Cited by 41 publications

References 80 publications

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

Inhibition of Oncogenic Kinases: An In Vitro Validated Computational Approach Identified Potential Multi-Target Anticancer Compounds

GPCR Modulation in Breast Cancer

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

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