Phosphopeptide selective coordination complexes as promising SRC homology 2 domain mimetics.
Src Homology 2 (SH2) domains are the paradigm of phosphotyrosine (pY) protein recognition modules and mediate numerous cancer-promoting protein-protein complexes. Effective SH2 domain mimicry with pY-binding coordination complexes offers a promising route to new and selective disruptors of pY-mediated protein-protein interactions. We herein report the synthesis and in vitro characterization of a library of coordination complex SH2 domain proteomimetics. Compounds were designed to interact with phosphopeptides via a two-point interaction, principally with pY, and to make secondary interactions with pY+2/3, thereby achieving sequence-selective discrimination. Here, we report that lead mimetics demonstrated high target phosphopeptide affinity (K(a) ∼ 10(7) M(-1)) and selectivity. In addition, biological screening in various tumor cells for anticancer effects showed a high degree of variability in cytotoxicity among receptors, which supported the proposed two-point binding mode. Several receptors potently disrupted cancer cell viability in breast cancer, prostate cancer, and acute myeloid leukemia cell lines.
Department of Chemical and Physical Sciences, University of Toronto, 3359 Mississauga Road North, Mississauga, Ontario L5L 1C6, Canada.
Joel A
JA
Drewry
Eugenia
E
Duodu
Amir
A
Mazouchi
Paul
P
Spagnuolo
Steven
S
Burger
Claudiu C
CC
Gradinaru
Paul
P
Ayers
Aaron D
AD
Schimmer
Patrick T
PT
Gunning
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D010748:Phosphopeptides / Q000737:chemistry* / Q000378:metabolism; D019000:Phosphotyrosine / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D062165:Receptors, Artificial / Q000138:chemical synthesis* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D018909:src Homology Domains / Q000235:genetics
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010748:Phosphopeptides; D062165:Receptors, Artificial; D054852:Small Molecule Libraries; D019000:Phosphotyrosine