Investigational New Drugs p. 1350 - 1364 (2020)
Update date:2022-07-29
Topics:
?upicka-S?owik, Agnieszka
Psurski, Mateusz
Grzywa, Renata
Cuprych, Monika
Ciekot, Jaros?aw
Goldeman, Waldemar
Wojaczyńska, El?bieta
Wojaczyński, Jacek
Oleksyszyn, Józef
Sieńczyk, Marcin
One of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based peptidyl antagonists of IAPs that mimic the endogenous Smac protein, which blocks the interaction between IAPs and caspases. Based on the structure of the IAP antagonist and recently reported thiadiazole derivatives, we designed and evaluated the biochemical properties of a series of phosphonic peptides bearing the N-Me-Ala-Val/Chg-Pro-OH motif (Chg: cyclohexylglycine). The ability of the obtained compounds to interact with the binding groove of the X-linked inhibitor of apoptosis protein baculovirus inhibitor of apoptosis protein repeat (XIAP BIR3) domain was examined by a fluorescence polarization assay, while their potential to induce autoubiquitination followed by proteasomal degradation of cellular IAP1 was examined using the MDA-MB-231 breast cancer cell line. The highest potency against BIR3 was observed among peptides containing C-terminal phosphonic phenylalanine analogs, which displayed nanomolar Ki values. Their antiproliferative potential as well as their proapoptotic action, manifested by an increase in caspase-3 activity, was examined using various cell lines.
View MoreCompro Shijiazhuang Fine Chemical Co., Ltd
Contact:0086-311-89689838
Address:Economic and Technological Development Zone of Shijiazhuang,Hebei
Shanghai Norky Pharmaceutical Co., LTD.
website:http://www.norkypharm.com
Contact:86-21-61075300
Address:1165 Jiangning Road, Office 1502, Shanghai, China
Antaeus Bio-technology Co., LTD(expird)
Contact:021-31252569
Address:shanghai pudong
Guangzhou Reachin Chemical Co., Ltd
Contact:+86-20-37087379 ext.604
Address:A122C-1, Tianyuan Plaza, 401 Tianyuan Rd., Tianhe, Guangzhou, China
Chemsigma International Co.,Ltd.
website:http://www.chemsigma.com
Contact:86-025-58748998
Address:Rm.705, 15th Building,Rd.Xinke II
Doi:10.1039/c8gc00477c
(2018)Doi:10.1021/jm010827j
(2001)Doi:10.1016/0960-894X(96)00003-0
(1996)Doi:10.1139/v61-033
(1961)Doi:10.1016/0957-4166(95)00050-Y
(1995)Doi:10.1021/ja01347a057
(1932)