Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma
Copyright © 2023 Elsevier Inc. All rights reserved..
Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding Gαq and Gα11 proteins are key genes to drive UM, making the selective inhibition of Gαq/11 proteins to be a potential therapeutic approach for combating UM. In this study, forty-six quinazoline derivatives were designed, synthesized, and assessed for their ability to inhibit Gαq/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against Gαq/11 proteins (IC50 = 9.4 μM) and two UM cell lines MP41 (IC50 = 6.7 μM) and 92.1 (IC50 = 3.7 μM). Being a small molecule inhibitor of Gαq/11 proteins, F33 could effectively suppress the activation of downstream signaling pathways in a dose-dependent manner, and significantly inhibits UM in vitro.F33 represents a promising lead compound for developing therapeutics for UM by targeting Gαq/11 proteins.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:143 |
|---|---|
| Enthalten in: |
Bioorganic chemistry - 143(2024) vom: 02. Feb., Seite 107005 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Fan, Guangjin [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 14.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bioorg.2023.107005 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365343838 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365343838 | ||
| 003 | DE-627 | ||
| 005 | 20240214232951.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bioorg.2023.107005 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1293.xml |
| 035 | |a (DE-627)NLM365343838 | ||
| 035 | |a (NLM)38043397 | ||
| 035 | |a (PII)S0045-2068(23)00666-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Fan, Guangjin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design, synthesis and evaluation of quinazoline derivatives as Gαq/11 proteins inhibitors against uveal melanoma |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.02.2024 | ||
| 500 | |a Date Revised 14.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Uveal melanoma (UM) represents the predominant ocular malignancy among adults, exhibiting high malignancy and proclivity for liver metastasis. GNAQ and GNA11 encoding Gαq and Gα11 proteins are key genes to drive UM, making the selective inhibition of Gαq/11 proteins to be a potential therapeutic approach for combating UM. In this study, forty-six quinazoline derivatives were designed, synthesized, and assessed for their ability to inhibit Gαq/11 proteins and UM cells. Compound F33 emerged as the most favorable candidate, and displayed moderate inhibitory activity against Gαq/11 proteins (IC50 = 9.4 μM) and two UM cell lines MP41 (IC50 = 6.7 μM) and 92.1 (IC50 = 3.7 μM). Being a small molecule inhibitor of Gαq/11 proteins, F33 could effectively suppress the activation of downstream signaling pathways in a dose-dependent manner, and significantly inhibits UM in vitro.F33 represents a promising lead compound for developing therapeutics for UM by targeting Gαq/11 proteins | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti-tumor effect | |
| 650 | 4 | |a Gαq/11 proteins inhibitors | |
| 650 | 4 | |a Quinazoline derivatives | |
| 650 | 4 | |a Structure-activity relationship studies | |
| 650 | 4 | |a Target verification | |
| 650 | 7 | |a GTP-Binding Protein alpha Subunits, Gq-G11 |2 NLM | |
| 650 | 7 | |a EC 3.6.5.1 |2 NLM | |
| 650 | 7 | |a Quinazolines |2 NLM | |
| 700 | 1 | |a Liu, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Xiao-Feng |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic chemistry |d 1986 |g 143(2024) vom: 02. Feb., Seite 107005 |w (DE-627)NLM012846570 |x 1090-2120 |7 nnns |
| 773 | 1 | 8 | |g volume:143 |g year:2024 |g day:02 |g month:02 |g pages:107005 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bioorg.2023.107005 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 143 |j 2024 |b 02 |c 02 |h 107005 | ||