Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant

被引：41

作者：

Radi, Marco ^{[1
,2
]}

Tintori, Cristina ^{[1
]}

Musumeci, Francesca ^{[3
]}

Brullo, Chiara ^{[3
]}

Zamperini, Claudio ^{[1
]}

Dreassi, Elena ^{[1
]}

Fallacara, Anna Lucia ^{[1
,4
]}

Vignaroli, Giulia ^{[1
]}

Crespan, Emmanuele

Zanoli, Samantha ^{[5
]}

Laurenzana, Ilaria ^{[6
]}

Filippi, Irene ^{[7
]}

Maga, Giovanni ^{[5
]}

Schenone, Silvia ^{[3
]}

Angelucci, Adriano ^{[8
]}

Botta, Maurizio ^{[1
,9
]}

机构：

[1] Univ Siena, Dipartimento Biotecnol Chim & Farm, I-53100 Siena, Italy

[2] Univ Parma, Dipartimento Farm, I-43124 Parma, Italy

[3] Univ Genoa, Dipartimento Farm, I-16132 Genoa, Italy

[4] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farm, I-00185 Rome, Italy

[5] IGM CNR, Ist Genet Mol, I-27100 Pavia, Italy

[6] IRCCS Referral Canc Ctr Basilicata CROB, Lab Preclin & Translat Res, Rionero In Vulture, PZ, Italy

[7] Univ Siena, Dipartimento Med Mol & Sviluppo, I-53100 Siena, Italy

[8] Univ Aquila, Dipartimento Sci Clin Applicate & Biotecnol, I-67100 Laquila, Italy

[9] Temple Univ, Coll Sci & Technol, Ctr Biotechnol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 13期

关键词：

CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITORS; BIOMOLECULAR SYSTEMS; PONATINIB AP24534; CRYSTAL-STRUCTURE; CELL-LINES; POTENT; RESISTANCE; IMATINIB; AGENTS;

D O I：

10.1021/jm400233w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from our in-house library of pyrazolo, [3,4-d]pyrimidines, a cross-docking simulation was conducted, on Bcr-Abl T315I mutant. Among the selected, compounds; (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the NI side chain phenyl,ring for the interaction with the T315I mutant. A series of 4;bromo derivatives was thin synthesized and biologically evaluated.: Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes.

引用

页码：5382 / 5394

页数：13

共 48 条

[21] Chronic myeloid leukemia: 2012 Update on diagnosis, monitoring, and management [J].