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Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.

Cumaraswamy AA, Lewis AM, Geletu M, Todic A, Diaz DB, Cheng XR, Brown CE, Laister RC, Muench D, Kerman K, Grimes HL, Minden MD, Gunning PT - ACS Med Chem Lett (2014)

Bottom Line: We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein.Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis.We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.

ABSTRACT
We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.

No MeSH data available.


Related in: MedlinePlus

(A) STAT5a’s SH2 domain with three binding pockets:hydrophilic,red; amphiphilic, green; amphiphilic, blue; (B) in silico docking of 1 interacting with R618, S622, and N639; 2 interacting with R618 and S622, as well as a cationic−πinteraction of the R1 benzyl with K644.
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fig2: (A) STAT5a’s SH2 domain with three binding pockets:hydrophilic,red; amphiphilic, green; amphiphilic, blue; (B) in silico docking of 1 interacting with R618, S622, and N639; 2 interacting with R618 and S622, as well as a cationic−πinteraction of the R1 benzyl with K644.

Mentions: While the activated STAT5–STAT5 dimer structure has yetto be solved, the pY binding pocket of the SH2 domain was identifiedby comparing and contrasting the structural architectures and bindingsites of 121 SH2 domain-containing proteins.18 SH2 domains are defined by an antiparallel β-sheet flankedby two α helices. The pY binds in a pocket located within theβB, C, and D strands. Specifically, a conserved R(XXX) residueon the βB strand participates in electrostatic interactionswith pY.19 Notably, STAT3′s structurewas resolved in both the unphosphorylated (PDB: 3CWB) and phosphorylated(PDB: 1BG1)states.20,21 Superimposition of structures revealed thatSTAT3′s SH2 domain structure is not significantly altered uponphosphopeptide binding.22 Thus, we reasonedthat the unphosphorylated STAT5 structure (PDB: 1Y1U) is suitable for in silico-based drug design. Analogous to the canonicalpY-SH2 domain binding, the STAT5 pY likely docks proximal to the conservedR618 (βB strand), making H-bonding/electrostatic interactionswith nearby polar residues, K600 (αA), T628 (βC), andS622 (βB and βC) Figure 2A.


Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.

Cumaraswamy AA, Lewis AM, Geletu M, Todic A, Diaz DB, Cheng XR, Brown CE, Laister RC, Muench D, Kerman K, Grimes HL, Minden MD, Gunning PT - ACS Med Chem Lett (2014)

(A) STAT5a’s SH2 domain with three binding pockets:hydrophilic,red; amphiphilic, green; amphiphilic, blue; (B) in silico docking of 1 interacting with R618, S622, and N639; 2 interacting with R618 and S622, as well as a cationic−πinteraction of the R1 benzyl with K644.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4234445&req=5

fig2: (A) STAT5a’s SH2 domain with three binding pockets:hydrophilic,red; amphiphilic, green; amphiphilic, blue; (B) in silico docking of 1 interacting with R618, S622, and N639; 2 interacting with R618 and S622, as well as a cationic−πinteraction of the R1 benzyl with K644.
Mentions: While the activated STAT5–STAT5 dimer structure has yetto be solved, the pY binding pocket of the SH2 domain was identifiedby comparing and contrasting the structural architectures and bindingsites of 121 SH2 domain-containing proteins.18 SH2 domains are defined by an antiparallel β-sheet flankedby two α helices. The pY binds in a pocket located within theβB, C, and D strands. Specifically, a conserved R(XXX) residueon the βB strand participates in electrostatic interactionswith pY.19 Notably, STAT3′s structurewas resolved in both the unphosphorylated (PDB: 3CWB) and phosphorylated(PDB: 1BG1)states.20,21 Superimposition of structures revealed thatSTAT3′s SH2 domain structure is not significantly altered uponphosphopeptide binding.22 Thus, we reasonedthat the unphosphorylated STAT5 structure (PDB: 1Y1U) is suitable for in silico-based drug design. Analogous to the canonicalpY-SH2 domain binding, the STAT5 pY likely docks proximal to the conservedR618 (βB strand), making H-bonding/electrostatic interactionswith nearby polar residues, K600 (αA), T628 (βC), andS622 (βB and βC) Figure 2A.

Bottom Line: We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein.Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis.We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.

ABSTRACT
We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.

No MeSH data available.


Related in: MedlinePlus