Identification of 7-Phenylaminothieno- [3,2-<i>b</i>]pyridine-6-carbonitriles as a New Class of Src Kinase Inhibitors

Boschelli, Diane H.; Wu, Botao; Sosa, Ana Carolina Barrios; Durutlic, Haris; Ye, Fei; Raifeld, Yuri E.; Golas, Jennifer M.; Boschelli, Frank

doi:10.1021/jm049237m

Cited by 46 publications

(34 citation statements)

References 22 publications

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“…Furthermore, SKI-606 also exerts activity against a variety of clinically relevant imatinib-resistant Abl domain mutations. [18][19][20][21] As a result, SKI-606 is currently under evaluation in phase 1/2 trials in CML patients resistant to or intolerant of imatinib. 22 However, the effects of SKI-606 on primary CML or normal primitive progenitor cells have not been described.…”

Section: Introductionmentioning

confidence: 99%

Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

König

Holyoake

Bhatia

2008

Blood

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Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34 ؉ cells and inhibited Src phosphorylation more potently than imatinib.However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits IntroductionTreatment with the Bcr-Abl kinase inhibitor imatinib mesylate (imatinib) has markedly improved the outcome for patients with chronic myeloid leukemia (CML). High response rates have been reported for CML patients in chronic phase (CP) of the disease, whereas patients with later stages of CML (accelerated phase and blast crisis) are prone to develop imatinib resistance. 1 Several mechanisms of resistance have been identified, including mutations in the BCR-ABL kinase domain, BCR-ABL amplification, and overexpression and abnormal, constitutive activation of growth stimulatory signaling pathways independent of Bcr-Abl. [2][3][4][5] Mathematical modeling of in vivo kinetics of response to imatinib, based on analysis of quantitative polymerase chain reaction (Q-PCR) data, suggests that imatinib inhibits production of differentiated leukemia cells but does not deplete leukemia stem cells. 6,7 Analysis of bone marrow samples from CML patients in complete remission on imatinib treatment confirms the persistence of leukemia stem and progenitor cells in this patient population. 8 Reports of recurrence occurring after discontinuation of imatinib therapy indicate that residual CML cells remaining after imatinib therapy possess pathogenic potential. 9,10 The eradication of malignant stem and progenitor cells thus appears to be necessary to improve the treatment outcome for these patients.We have shown that suppression of CML progenitor growth by imatinib is primarily accomplished through inhibition of abnormally increased proliferation rather than through induction of apoptosis, and that nondividing primitive progenitors are insensitive to imatinib-induced apoptosis. 11,12 Our studies indicate that inherent resistance of quiescent CML progenitors to apoptosis plus microenvironmental activation of signaling pathways that contribute to maintenance of viability in imatinib-treated CML progenitors may be potential mechanisms underlying the persistence of malignant proge...

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Section: Introductionmentioning

confidence: 99%

Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

König

Holyoake

Bhatia

2008

Blood

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“…[1][2][3][4][5][6] Consequently, a sizable portion of recent US patents reports on organic process development of aromatic heterocycles. [7,8] A useful synthetic tool for the modification of such compounds is the SuzukiMiyaura coupling, [9,10] which has been applied for the preparation of arylpyridines, [11,12] bipyridines, [11][12][13][14][15] arylpyrimidines, [16][17][18] pyridopyridines [11,12,[19][20][21] and aryltriazines, [22,23] the synthesis of nucleosides [24,25] or the introduction of thiophene, [26,27] benzothiazole [28] or indolyl [29][30][31][32] moieties.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

Fleckenstein

Plenio

2008

Chemistry A European J

120

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A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl)phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na(2)PdCl(4)] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridine- or indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol % of Pd catalyst at 100 degrees C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol % of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

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“…As an example, the phenylaminothieno[3,2-b]pyridine-6-carbonitrile 13 is a good dual Abl/Src inhibitor. 107 Astra-Zeneca researchers synthesized several anilino-quinazolines as potent Src inhibitors 108 and successive modifications of this scaffold afforded the dual Src/Abl ATP-competitive inhibitor 14 (AZD0530) (Fig. 3) bearing a C5 tetrahydropyran-4-yloxy substituent and a C7 solubilizing basic chain.…”

Section: B Quinoline and Quinazoline Derivativesmentioning

confidence: 99%

New insights into small‐molecule inhibitors of Bcr‐Abl

Schenone

Bruno

Radi

et al. 2010

Medicinal Research Reviews

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Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

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Identification of 7-Phenylaminothieno- [3,2-b]pyridine-6-carbonitriles as a New Class of Src Kinase Inhibitors

Cited by 46 publications

References 22 publications

Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

New insights into small‐molecule inhibitors of Bcr‐Abl

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