Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG..
Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted us to model this interesting target using our QSAR-guided selection of docking-based pharmacophores approach where numerous pharmacophores are extracted from docked ligand poses and allowed to compete within the context of QSAR. The optimal pharmacophore was sterically-refined, validated by receiver operating characteristic (ROC) curve analysis and used as virtual search query to screen the National Cancer Institute (NCI) database for new promising anti-PKN2 leads of novel chemotypes. Three low micromolar hits were identified with IC50 values ranging between 9.9 and 18.6 µM. Pharmacological assays showed promising cytotoxic properties for active hits in MTT and wound healing assays against MCF-7 and PANC-1 cancer cells.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
---|---|
Enthalten in: |
Molecular diversity - 27(2023), 1 vom: 04. Feb., Seite 443-462 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Al-Sha'er, Mahmoud A [VerfasserIn] |
---|
Links: |
---|
Themen: |
Anticancer |
---|
Anmerkungen: |
Date Completed 28.02.2023 Date Revised 28.02.2023 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1007/s11030-022-10434-4 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM340359005 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM340359005 | ||
003 | DE-627 | ||
005 | 20231226005013.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1007/s11030-022-10434-4 |2 doi | |
028 | 5 | 2 | |a pubmed24n1134.xml |
035 | |a (DE-627)NLM340359005 | ||
035 | |a (NLM)35507210 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Al-Sha'er, Mahmoud A |e verfasserin |4 aut | |
245 | 1 | 0 | |a Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores |
264 | 1 | |c 2023 | |
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 28.02.2023 | ||
500 | |a Date Revised 28.02.2023 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG. | ||
520 | |a Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted us to model this interesting target using our QSAR-guided selection of docking-based pharmacophores approach where numerous pharmacophores are extracted from docked ligand poses and allowed to compete within the context of QSAR. The optimal pharmacophore was sterically-refined, validated by receiver operating characteristic (ROC) curve analysis and used as virtual search query to screen the National Cancer Institute (NCI) database for new promising anti-PKN2 leads of novel chemotypes. Three low micromolar hits were identified with IC50 values ranging between 9.9 and 18.6 µM. Pharmacological assays showed promising cytotoxic properties for active hits in MTT and wound healing assays against MCF-7 and PANC-1 cancer cells | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Anticancer | |
650 | 4 | |a PKN2 | |
650 | 4 | |a QSAR guided selection of pharmacophores | |
650 | 4 | |a Structure based modeling | |
650 | 7 | |a Ligands |2 NLM | |
650 | 7 | |a Protein Kinase C |2 NLM | |
650 | 7 | |a EC 2.7.11.13 |2 NLM | |
650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
650 | 7 | |a protein kinase N |2 NLM | |
650 | 7 | |a EC 2.7.1.- |2 NLM | |
700 | 1 | |a Basheer, Haneen A |e verfasserin |4 aut | |
700 | 1 | |a Taha, Mutasem O |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Molecular diversity |d 1997 |g 27(2023), 1 vom: 04. Feb., Seite 443-462 |w (DE-627)NLM091914590 |x 1573-501X |7 nnns |
773 | 1 | 8 | |g volume:27 |g year:2023 |g number:1 |g day:04 |g month:02 |g pages:443-462 |
856 | 4 | 0 | |u http://dx.doi.org/10.1007/s11030-022-10434-4 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 27 |j 2023 |e 1 |b 04 |c 02 |h 443-462 |