Multi-Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation.

Advanced Science
Liting WangYourong Duan

Abstract

The binding of amyloid precursor protein (APP) expressed on tumor cells to death receptor 6 (DR6) could initiate the necroptosis pathway, which leads to necroptotic cell death of vascular endothelial cells (ECs) and results in tumor cells (TCs) extravasation and metastasis. This study reports the first inhibitor of DR6/APP interaction as a novel class of anti-hematogenous metastatic agent. By rationally utilizing three combined strategies including selection based on phage display library, d-retro-inverso modification, and multiple conjugation of screened peptidomimetic with 4-arm PEG, the polymer-peptidomimetic conjugate PEG-tAHP-DRI (tetra-(D-retro-inverso isomer of AHP-12) substitued 4-arm PEG5k ) is obtained as the most promising agent with the strongest binding potency (KD  = 51.12 × 10-9  m) and excellent pharmacokinetic properties. Importantly, PEG-tAHP-DRI provides efficient protection against TC-induced ECs necroptosis both in vitro and in vivo. Moreover, this ligand exhibits prominent anti-hematogenous metastatic activity in serval different metastatic mouse models (B16F10, 4T1, CT26, and spontaneous lung metastasis of 4T1 orthotopic tumor model) and displays no apparent detrimental effects in preliminary safety evalu...Continue Reading

References

Oct 3, 2001·Nature Biotechnology·M MourezR J Collier
Mar 26, 2003·Seminars in Cancer Biology·Anning Lin, Michael Karin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Jan 13, 2006·Nature Chemical Biology·Alexei DegterevJunying Yuan
Jul 25, 2008·The Journal of Biological Chemistry·Gopal Thinakaran, Edward H Koo
Feb 20, 2009·Nature·Anatoly NikolaevMarc Tessier-Lavigne
Jan 5, 2010·Current Opinion in Cell Biology·Dana E Christofferson, Junying Yuan
Jul 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Min LiuWuyuan Lu
Sep 9, 2010·Nature Reviews. Molecular Cell Biology·Peter VandenabeeleGuido Kroemer
Oct 29, 2010·Nature Communications·Christoph J WienkenStefan Duhr
Jun 16, 2011·Molecular Cancer·Brian A ZabelThomas J Schall
Oct 18, 2011·Cell·Scott Valastyan, Robert A Weinberg
Sep 25, 2012·Angewandte Chemie·Susanne A I SeidelPhilipp Baaske
Oct 13, 2012·Cancer Letters·Georg F Weber
Nov 10, 2013·Nature Medicine·Liling WanYibin Kang
Nov 23, 2013·Nature Reviews. Cancer·Nicolas ReymondAnne J Ridley
Aug 27, 2014·Nature Reviews. Cancer·Catherine Alix-Panabières, Klaus Pantel
Jan 17, 2015·Nature·Manolis Pasparakis, Peter Vandenabeele
Apr 9, 2015·EMBO Molecular Medicine·Alexander CarpinteiroErich Gulbins
Jan 23, 2016·Nature·Joan Massagué, Anna C Obenauf
Feb 9, 2017·Biological Psychiatry·Emilie Trillaud-Doppia, Jannic Boehm
Mar 7, 2017·Current Drug Targets·Yingzhi ChenYongzhuo Huang
Mar 18, 2017·Nature Reviews. Cancer·Héctor PeinadoDavid Lyden
Dec 15, 2017·Cell Death and Differentiation·Chao LiuGavin S Dawe
Feb 13, 2018·Cell Death & Disease·Sofie MartensPeter Vandenabeele
Dec 1, 2018·Ageing Research Reviews·Fernando GalvãoIonara Rodrigues Siqueira
Mar 7, 2019·Current Topics in Medicinal Chemistry·Ankit GaneshpurkarSushil K Singh
May 19, 2019·Cell Death and Differentiation·Snahel PatelDomagoj Vucic
Jul 14, 2019·Biophysics Reviews·Lloyd Mabonga, Abidemi Paul Kappo

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