Search results for: Stephanos Ioannidis

Items from 1 to 12 out of 12 results

article

Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering

Jeffrey W. Johannes, Lynsie Almeida, Kevin Daly, Andrew D. Ferguson, more

Bioorganic & Medicinal Chemistry Letters > 2015 > 25 > 24 > 5743-5747

The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic...

article

Towards the next generation of dual Bcl-2/Bcl-xL inhibitors

Jeffrey G. Varnes, Thomas Gero, Shan Huang, R. Bruce Diebold, more

Bioorganic & Medicinal Chemistry Letters > 2014 > 24 > 14 > 3026-3033

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-x _L in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding...

article

Discovery of novel Jak2–Stat pathway inhibitors with extended residence time on target

Huiping Guan, Michelle L. Lamb, Bo Peng, Shan Huang, more

Bioorganic & Medicinal Chemistry Letters > 2013 > 23 > 10 > 3105-3110

The discovery of the activating mutation V617F in the JH2 domain of Jak2 and the modulation of oncogenic Stat3 by Jak2 inhibitors have spurred a great interest in the inhibition of the Jak2/Stat pathway in oncology. In this Letter, we communicate the discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives. The rationale, synthesis and biological evaluation...

article

In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors

Tao Wang, Stephanos Ioannidis, Lynsie Almeida, Michael H. Block, more

Bioorganic & Medicinal Chemistry Letters > 2011 > 21 > 10 > 2958-2961

Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.

article

Discovery of 5-Chloro- N ² -[(1 S )-1-(5-fluoropyrimidin-2-yl)ethyl]- N ⁴ -(5-methyl-1 H -pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a Novel Inhibitor of the Jak/Stat Pathway

Stephanos Ioannidis, Michelle L. Lamb, Tao Wang, Lynsie Almeida, more

Journal of Medicinal Chemistry > 2011 > 54 > 1 > 262 - 276

article

Replacement of pyrazol-3-yl amine hinge binder with thiazol-2-yl amine: Discovery of potent and selective JAK2 inhibitors

Stephanos Ioannidis, Michelle L. Lamb, Lynsie Almeida, Huiping Guan, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 5 > 1669-1673

Thiazol-2-yl amine was identified as an isosteric replacement for pyrazol-3-yl amine during our efforts to identify potent and selective JAK2 inhibitors. The rationale, synthesis and biological evaluation of several analogs is reported, along with the in vivo evaluation of the lead compounds.

article

The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

Michael Hedvat, Dennis Huszar, Andreas Herrmann, Joseph M. Gozgit, more

Cancer Cell > 2009 > 16 > 6 > 487-497

Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition...

article

Discovery of pyrazol-3-ylamino pyrazines as novel JAK2 inhibitors

Stephanos Ioannidis, Michelle L. Lamb, Audrey M. Davies, Lynsie Almeida, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 23 > 6524-6528

The design, synthesis and biological evaluation of a series of pyrazol-3-ylamino pyrazines as potent and selective JAK2 kinase inhibitors is reported, along with the pharmacokinetic and pharmacodynamic properties of lead compounds.

article

Identification of amidoheteroaryls as potent inhibitors of mutant (V600E) B-Raf kinase with in vivo activity

Paul D. Lyne, Brian Aquila, Donald J. Cook, Les A. Dakin, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 3 > 1026-1029

A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.

article

Pyridyl and thiazolyl bisamide CSF-1R inhibitors for the treatment of cancer

David A. Scott, Brian M. Aquila, Geraldine A. Bebernitz, Donald J. Cook, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 17 > 4794-4797

The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.

article

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors

James W. Janetka, Lynsie Almeida, Susan Ashwell, Patrick J. Brassil, more

Bioorganic & Medicinal Chemistry Letters > 2008 > 18 > 14 > 4242-4248

Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.

article

4-(Phenylsulfonyl)-4-lithiocyclopentene as a nucleophilic 2-pentene-1,5-dial synthetic equivalent. An aziridine-based synthetic approach to (−)-alstonerine

Paul Cox, Donald Craig, Stephanos Ioannidis, Volker S. Rahn

Tetrahedron Letters > 2005 > 46 > 27 > 4687-4690

Reaction of 4-lithio-4-(phenylsulfonyl)cyclopentene with an l-tryptophan-derived N-tosylaziridine provides an adduct. Oxidative cleavage of the cyclopentene double bond provides a dialdehyde, which enters into acid-catalysed Pictet–Spengler-type bicyclisation to give a tetracyclic aldehyde. Completely regioselective silyl dienol ether formation followed by completely stereoselective hetero-Diels–Alder...

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