公开(公告)号：US08084455B2

公开(公告)日：2011-12-27

申请号：US12293985

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/497

CPC分类号： A61K31/4162 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377

摘要： The invention provides low molecular weight compounds, namely tetrahydropyrrolo[3,4-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即四氢吡咯并[3,4-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US20100035876A1

公开(公告)日：2010-02-11

申请号：US12293985

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/5377 ,  C12N5/00 ,  A61K31/496 ,  A61K31/454 ,  G01N33/53

CPC分类号： A61K31/4162 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377

摘要： The invention provides low molecular weight compounds, namely tetrahydropyrrolo[3,4-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即四氢吡咯并[3,4-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US07803829B2

公开(公告)日：2010-09-28

申请号：US12295447

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/415

CPC分类号： A61K31/4162 ,  A61K31/44

摘要： The invention provides low molecular weight compounds, namely 1H-thieno[2,3-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即1H-噻吩并[2,3-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US20100022532A1

公开(公告)日：2010-01-28

申请号：US12295447

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/4162 ,  A61K31/5377 ,  A61K31/454 ,  A61K31/496

CPC分类号： A61K31/4162 ,  A61K31/44

摘要： The invention provides low molecular weight compounds, namely 1H-thieno[2,3-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即1H-噻吩并[2,3-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。