Phosphopeptide Selective Coordination Complexes as Promising Src Homology 2 Domain Mimetics Journal Articles uri icon

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abstract

  • 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.

authors

  • Drewry, Joel A
  • Duodu, Eugenia
  • Mazouchi, Amir
  • Spagnuolo, Paul
  • Burger, Steven
  • Gradinaru, Claudiu C
  • Ayers, Paul
  • Schimmer, Aaron D
  • Gunning, Patrick T

publication date

  • August 6, 2012

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