4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies

Bellacasa, Raimon Puig de la; Roué, Gaël; Balsas, Patricia; Pérez-Galán, Patricia; Teixidó, Jordi; Colomer, Dolors; Borrell, José I.

doi:10.1016/j.ejmech.2014.09.018

Cited by 26 publications

(33 citation statements)

References 28 publications

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“…We identified IQS019 (compound 19) as a unique molecule with affinity for the three BCR kinases [13]. In the present work, we confirm the inhibitory property of the compound against Btk, Syk and Lyn, as well as its selective antitumoral effect in B lymphoid cells, especially in MCL and FL cell lines, and independently of the response to ibrutinib.…”

Section: Discussionsupporting

confidence: 77%

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

et al. 2017

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BackgroundPharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton’s kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents.MethodsWe evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma.ResultsIQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest.ConclusionsThese results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0447-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

et al. 2017

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“…On the contrary, in the case of the structures 10 (C5-C6 double bond), 53.53% present only a substituent at C6 (R 5 = H) with the following distribution referring to the total number of structures: 44.46% carbon substituent [55,56] (32.12% phenyl ring [42,57,58]), 4.70% oxygen substituent [59,60], and 1.00% nitrogen substituent [32,61]. In 7.05% of the structures there is a substituent at C5 (R 6 = H) with the following distribution referring to the total number of structures: 4.16% carbon substituent [62,63] (0.10% phenyl ring [16,56]), 0.47% oxygen substituent [56,64], and 2.39% nitrogen substituent [64,65].…”

Section: Substitution Pattern At C5 and C6mentioning

confidence: 99%

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

et al. 2019

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Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

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“…Since the discovery of a protein kinase in 1954 [1], the field of protein kinase drug discovery has advanced enormously [2][3][4][5]. Early studies were focused on receptor tyrosine kinases including EGFR, VEGFR, and PDGFR, especially as therapeutic targets for cancer.…”

Section: Introductionmentioning

confidence: 99%

“…General Synthesis of N-(4 or 5-amino-2-methylphenyl)-5-methylisoxazole-4-carboxamide (4a-4b)5-methyl-N-(2-methyl-4 or 5-nitrophenyl) isoxazole-4-carboxamide (3a or 3b) (460 mg, 1.76mmol) 80mmol) in EtOH (3.5 mL) was stirredat 80 o C. Stirring was continued for 7h and the clear solution was cooled to room temperature. Solvent was removed in vacuo and was then poured into ice.…”

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confidence: 99%

Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors

Jung

Yang

et al. 2015

European Journal of Medicinal Chemistry

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4-Amino-2-arylamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7-(8H)-ones as BCR kinase inhibitors for B lymphoid malignancies

Cited by 26 publications

References 28 publications

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors

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