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001-es BibID:	BIBFORM082393
035-os BibID:	(PMID)31717403 (cikkazonosító)5590 (scopus)85074657590 (wos)000502786800072
Első szerző:	Murányi József
Cím:	Novel Crizotinib-GnRH conjugates revealed the significance of lysosomal trapping in GnRH-based drug delivery systems / József Murányi, Attila Varga, Pál Gyulavári, Kinga Pénzes, Csilla E. Németh, Miklós Csala, Lilla Pethő, Antal Csámpai, Gábor Halmos, István Peták, István Vályi-Nagy
Dátum:	2019
ISSN:	1661-6596 1422-0067
Megjegyzések:	Several promising anti-cancer drug-GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)- or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [d-Lys6]-GnRH-I targeting peptide. Our most prominent crizotinib-GnRH conjugates, the amide-bond-containing [d-Lys6(crizotinib)]-GnRH-I and the ester-bond-containing [d-Lys6(MJ55)]-GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib-GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets-the ATP-binding site of RTKs- and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib-GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug-GnRH conjugates.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk GnRH GnRHR NSCLC c-Met conjugate crizotinib endocytosis galectin lysosome permeability targeted drug delivery
Megjelenés:	International Journal of Molecular Sciences. - 20 : 22 (2019), p. 1-23. -
További szerzők:	Varga Attila (biokémikus) Gyulavári Pál Pénzes Kinga Németh Csilla Csala Miklós Pethő Lilla Csámpai Antal Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Peták István Vályi-Nagy István
Pályázati támogatás:	NVKP_16-1-2016-0005 Egyéb K-124813 Egyéb K-128785 Egyéb GINOP-2.3.2-15-2016-00043 GINOP
Internet cím:	DOI Intézményi repozitóriumban (DEA) tárolt változat
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