A tool for the selective sequestration of ATP and PPi to aid in-solution phosphopeptide detection assays.

The presence of small phospho-anions, such as PPi and ATP in protein samples often complicates the robust detection of phosphoproteins by metal-based chemosensors and receptors. We herein report the development of a bis(Zn(2+)-cyclen)-triethylbenzene scaffold which can selectively sequester PPi and ATP without affecting the detection of a di-phosphorylated peptide by a ProxyPhos chemosensor.

Progress towards the development of SH2 domain inhibitors.

Src homology 2 (SH2) domains are 100 amino acid modular units, which recognize and bind to tyrosyl-phosphorylated peptide sequences on their target proteins, and thereby mediate intracellular protein-protein interactions. This review summarizes the progress towards the development of synthetic agents that disrupt the function of the SH2 domains in different proteins as well as the clinical relevance of targeting a specific SH2 domain. Since 1986, SH2 domains have been identified in over 110 human proteins, including kinases, transcription factors, and adaptor proteins. A number of these proteins are over-activated in many diseases, including cancer, and their function is highly dependent on their SH2 domain. Thus, inhibition of a protein's function through disrupting that of its SH2 domain has emerged as a promising approach towards the development of novel therapeutic modalities. Although targeting the SH2 domain is a challenging task in molecular recognition, the progress reported here demonstrates the feasibility of such an approach.

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.

Understanding the delivery of a Canadian-based after-school STEM program: a case study.

BACKGROUND: Due to the rising demands for a Canadian workforce with science, technology, engineering, and math (STEM)-related education, there is a need to increase youth engagement in STEM education and programming. Research, however, has shown that youth residing in low-income communities are disproportionately affected by psychosocial barriers, which often inhibit meaningful engagement in STEM programming. Visions of Science Network for Learning (VoSNL) was designed and implemented to address these existing barriers. VoSNL is a charitable organization in Southern Ontario, Canada, that provides weekly community-based STEM programming to low-income and marginalized youth during out-of-school time. VoSNL programming is delivered directly within the community and is free-of-charge for all youth in order to minimize barriers of physical and financial accessibility. The purpose of this report was to provide a detailed description of a core program within VoSNL-Community Science Clubs-and summarize the findings of a process evaluation, specifically the successes and challenges of implementing a community-based, out-of-school STEM program. RESULTS: Program successes are outlined along with the challenges that have been identified through program implementation. Successes include (a) delivering the program within a community context, (b) opportunities for consistent engagement, and (c) establishing positive youth-staff relationships. Challenges include (a) navigating community-based issues, (b) conducting outreach and promotion, and (c) accommodating a wide age range of youth. Further, lessons learned from an evaluation of program implementation are also discussed. CONCLUSIONS: This report provides one of the first program descriptions and process evaluations of a community-based, youth-focused STEM program within a Canadian context. The findings in this report have helped to improve the delivery and evaluation of the VoSNL program and may act as a catalyst for program expansion to reach more youth in marginalized communities. Further, the findings can also provide a strong framework for programmers interested in implementing STEM youth programming in a community context, assist in the replication of similar models in other locations, and enhance STEM learning amongst youth.

Selective detection of tyrosine-containing proximally phosphorylated motifs using an antenna-free Tb³âº luminescent sensor.

We herein report the first application of Tb(3+) for the selective detection of an important subset of the phosphoproteome, namely, proximally di-phosphorylated peptide motifs where at least one phosphorylated residue is tyrosine.