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Patrick T. Gunning - One of the best experts on this subject based on the ideXlab platform.
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Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, Peibin Yue, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 Protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
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small molecule STAT5 sh2 domain inhibitors exhibit potent antileukemia activity
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (Ki 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosi...
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Progress towards direct inhibitors of STAT5 Protein.
Hormone Molecular Biology and Clinical Investigation, 2012Co-Authors: Abbarna A. Cumaraswamy, Patrick T. GunningAbstract:Abstract Molecular approaches to inhibit STAT5 signaling have been hailed as a viable targeted anticancer therapy. In particular, many drugs and drug candidates have been developed to successfully inhibit upstream effectors of STAT5 by indirectly targeting cell surface receptors and Protein kinases (FLT-3, JAK2, and BCR-ABL). Indirect strategies have yielded potent agents, such as imatinib, AC2207, and EXEL823 which effectively silence STAT5 activity but which suffer from off-target effects and toxicity. This article will focus on reviewing the current literature pertaining to direct inhibitors of STAT5 Protein and assess the prospects for a future STAT5-targeting therapeutic.
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Inhibitors of STAT5 Protein signalling
MedChemComm, 2011Co-Authors: Abbarna A. Cumaraswamy, Aleksandra Todic, Diana Resetca, Mark D. Minden, Patrick T. GunningAbstract:Evidence shows that signal transducer and activator of transcription 5 (STAT5) Protein, a member of the STAT family of signalling Proteins, plays a pivotal role in the progression of many human cancers including acute myeloid leukemias and prostate cancer. This mini-review outlines progress made towards identifying agents capable of silencing aberrant STAT5 signalling.
Rob C. Laister - One of the best experts on this subject based on the ideXlab platform.
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285 A nanomolar-potency small molecule inhibitor of the STAT5 Protein
European Journal of Cancer, 2014Co-Authors: A.a. Cumaraswamy, Mulu Geletu, Diego B. Diaz, Xin R. Cheng, Carla E. Brown, Rob C. Laister, David E. Muench, A. Lewis, A. Todic, Kagan KermanAbstract:Cancer cells produce and degrade Proteins more rapidly than most normal cells, and are in turn more sensitive to changes in Protein regulation. Similarly to secretory cells, cancer cells have the propensity to undergo endoplasmic reticulum (ER) stress due to higher Protein turnover that, if left uncorrected, can result in apoptosis. To avoid these fates, cells have developed support systems such as the conjugation of the ubiquitin-fold modifier 1 (UFM1) ubiquitin-like Protein to other Protein targets, which has been implicated in counteracting apoptotic ER stress in pancreatic secretory cells. Our research has recently focused on the development of the first inhibitor of the UFM1 pathway by targeting its E1 enzyme, UBA5, in order to counteract the anti-apoptotic effects of this system and to further study the role of UFM1 conjugation in cancer cells. We have successfully identified a lead inhibitor, 5C-Z, which incorporates an adenosine moiety coupled to a zinc(II) polyazamacrocylic coordination complex. Through enzymatic assays that evaluate the transthiolation ability of UBA5 in the first step of UFM1 activation, our inhibitor exhibits low micromolar activity against UBA5 while demonstrating potent selectivity over other E1 enzymes (>20fold). Kinetic assays reveal that 5C-Z acts non-competitively on UBA5, indicating that the compound could possibly be binding to and inhibiting the “inactive” subunit of the UBA5 homodimer. Furthermore, treatment of lung and leukemia cells that exhibit high levels of UBA5 Protein expression leads to a decrease in cell proliferation yet does not induce cell death in diseased or healthy cells, up to 200 mM. This novel strategy of inhibiting UBA5 and UFMylation would make cancer cells that are highly dependent on this system more susceptible to treatment regimens of principle drugs, which could lead to the use of milder drug dosing strategies. Our novel inhibitors produced from this research can be used as a probe to further investigate the role of E1 activating enzymes in cancer progression.
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Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.
ACS Medicinal Chemistry Letters, 2014Co-Authors: Abbarna A. Cumaraswamy, Aleksandra Todic, Andrew M. Lewis, Mulu Geletu, Diego B. Diaz, Xin R. Cheng, Carla E. Brown, Rob C. Laister, David E. Muench, Kagan KermanAbstract: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.
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Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, Peibin Yue, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 Protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
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small molecule STAT5 sh2 domain inhibitors exhibit potent antileukemia activity
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (Ki 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosi...
Brent D. G. Page - One of the best experts on this subject based on the ideXlab platform.
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Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, Peibin Yue, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 Protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
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small molecule STAT5 sh2 domain inhibitors exhibit potent antileukemia activity
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (Ki 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosi...
Mark D. Minden - One of the best experts on this subject based on the ideXlab platform.
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small molecule STAT5 sh2 domain inhibitors exhibit potent antileukemia activity
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (Ki 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosi...
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Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, Peibin Yue, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 Protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
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Inhibitors of STAT5 Protein signalling
MedChemComm, 2011Co-Authors: Abbarna A. Cumaraswamy, Aleksandra Todic, Diana Resetca, Mark D. Minden, Patrick T. GunningAbstract:Evidence shows that signal transducer and activator of transcription 5 (STAT5) Protein, a member of the STAT family of signalling Proteins, plays a pivotal role in the progression of many human cancers including acute myeloid leukemias and prostate cancer. This mini-review outlines progress made towards identifying agents capable of silencing aberrant STAT5 signalling.
Haytham Khoury - One of the best experts on this subject based on the ideXlab platform.
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Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, Peibin Yue, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 Protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
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small molecule STAT5 sh2 domain inhibitors exhibit potent antileukemia activity
Journal of Medicinal Chemistry, 2012Co-Authors: Brent D. G. Page, Mark D. Minden, Rob C. Laister, Haytham Khoury, Steven Fletcher, Megan Vellozo, Alessia Manzoli, James Turkson, Patrick T. GunningAbstract:A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) Protein, a key member of the STAT family of signaling Proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, STAT5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 Protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 Proteins for SH2 domain selectivity. We herein report the identification of several potent (Ki 3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosi...