C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

<p>The interleukin-2-inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in human. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure-activity relationship study of a new series of 5'-(benzo[d][1,3]dioxol-5-yl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one linked with N-acyl and C-5 aryl-substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds <b>11</b>, <b>12</b>, <b>14</b> and <b>15</b> showed high antiproliferative activity against ITK and BTK cell lines. Compounds <b>11</b> and <b>12</b> with a C-5 benzodioxole group and gem-dialkyl group attached to carbonyl on piperidine were highly effective in ITK-high Jurkat and CEM cell lines, and compound <b>14, </b>a<strong> </strong>biotin analogue, was identified as a good inhibitor of BTK-high RAMOS cells. Compound <b>15 </b>with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines.<b> </b></p>

Structure and function of Tec family kinase Itk

Itk is a member of the Tec family of kinases that is expressed predominantly in T cells. Itk regulates the T cell receptor signaling pathway to modulate T cell development and T helper cell differentiation, particularly Th2 differentiation. Itk is also important for the development and function of iNKT cells. In this review we discuss current progress on our understanding of the structure, activation and signaling pathway of Itk, in addition to inhibitors that have been developed, which target this kinase. We also place in context the function of Itk, available inhibitors and potential use in treating disease.

Tyrosine kinase Btk regulates E-selectin–mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways

Selectins mediate leukocyte rolling, trigger β2-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)–dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) γ2– and phosphoinositide 3-kinase (PI3K) γ–dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP3), and inducing E-selectin–mediated slow rolling. Inhibition of this signal-transduction pathway diminished Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk−/− and Plcg2−/− mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.