Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Characterization of Dimeric and Tetrameric 12-Mers Targeting the EphA2-LBD
2.2. Dimeric Agents May Promote Dimerization of EphA2-LBD
2.3. Dimeric and Tetrameric Compounds Are Potent Agonists of EphA2 Signaling
2.4. Cell Migration Studies
3. Materials and Methods
3.1. Synthetic Chemistry
3.2. Molecular Modeling and In Vitro Studies
3.3. Cell Lines, Cell Culture, and Antibodies
3.4. Establishment of an EphA2 Knocked-Out Pancreatic Cancer Cell Line
3.5. Cell Migration Assays
3.6. Immunoblotting Assays
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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ID | Sequence | IC50 (nM) (DELFIA) |
---|---|---|
123B9 | (4F,3ClPhOCH2CO)SAYPDSVP(Nle)(Hsr)S-CONH2 | 6500 ± 1700, n = 2 |
YSA | H2N-YSAYPDSVPMMS-CONH2 | 16200 ± 800, n = 14 |
135B12 | H2N-YSAYPDSVPFRP-CONH2 | 1600 ± 200, n = 16 |
135C11 (dimer of 135B12) | (H2N-YSAYPDSVPFRPG)2-K-CONH2 | 700 ± 100, n = 4 |
135C12 (dimer of 135B12) | (H2N-YSAYPDSVPFRP-βAla)2-K-CONH2 | 300 ± 100, n = 3 |
135D1 (dimer of 135B12) | (H2N-YSAYPDSVPFRP-GABA)2-K-CONH2 | 400 ± 200, n = 3 |
135E2 | (4F,3Cl-PhOCH2CO)SAYPDSVPFRP-CONH2 | 3100 ± 600, n = 3 |
135G3 | (4F,3Cl-PhOCH2CO)SAYPDSV(Hyp)(4Cl-Phe)RP-CONH2 | 600 ± 100, n = 6 |
135G4 (dimer of 135G3) | ((4F,3Cl-PhOCH2CO)SAYPDSV(Hyp)(4Cl-Phe)RPG)2-K-CONH2 | 130 ± 2 n = 1 |
135H11 | (3-CH3,6,7-OCH3,Benzofuranoic acid)LA(4-CH3-Tyr)PDA V(Hyp)(4Cl-Phe)RP-CONH2 | 130 ± 1, n = 4 |
135H12 (dimer of 135H11) | ((3-CH3,6,7-OCH3,Benzofuranoic acid)LA(4-CH3-Tyr)PDAV(Hyp)(4Cl-Phe) RPG)2-K-CONH2 | 150 ± 60, n = 3 |
135I1 (tetramer of 135H11) | {[(3-CH3,6,7-OCH3,Benzofuranoic acid)LA(4-CH3-Tyr)PDAV(Hyp)(4Cl-Phe)RPG]2-K-K}2-K-CONH2 | 60 ± 10, n = 2 |
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Salem, A.F.; Gambini, L.; Udompholkul, P.; Baggio, C.; Pellecchia, M. Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents. Pharmaceuticals 2020, 13, 90. https://doi.org/10.3390/ph13050090
Salem AF, Gambini L, Udompholkul P, Baggio C, Pellecchia M. Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents. Pharmaceuticals. 2020; 13(5):90. https://doi.org/10.3390/ph13050090
Chicago/Turabian StyleSalem, Ahmed F., Luca Gambini, Parima Udompholkul, Carlo Baggio, and Maurizio Pellecchia. 2020. "Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents" Pharmaceuticals 13, no. 5: 90. https://doi.org/10.3390/ph13050090