Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)

被引：22

作者：

Fang, Chao ^{[1
]}

D'Souza, Brendan ^{[1
]}

Thompson, Christopher F. ^{[1
]}

Clifton, Matthew C. ^{[4
]}

Fairman, James W. ^{[4
]}

Fulroth, Ben ^{[1
]}

Leed, Alison ^{[1
]}

McCarren, Patrick ^{[1
]}

Wang, Lili ^{[1
]}

Wang, Yikai ^{[1
]}

Feau, Clementine ^{[1
]}

Kaushik, Virendar K. ^{[1
]}

Palmer, Michelle ^{[1
]}

Wei, Guo ^{[1
]}

Golub, Todd R. ^{[1
,2
,3
]}

Hubbard, Brian K. ^{[1
]}

Serrano-Wu, Michael H. ^{[1
]}

机构：

[1] Broad Inst, Cambridge, MA 02142 USA

[2] Dana Farber Canc Inst, Boston, MA 02215 USA

[3] Howard Hughes Med Inst, Boston, MA 02215 USA

[4] Beryllium, Bedford, MA 01730 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 12期

关键词：

MCL1; myeloid cell leukemia 1; sp(3)-rich; biophysical validation; ISOTHERMAL TITRATION CALORIMETRY; BCL-2 PROTEIN FAMILY; DRUG DISCOVERY; INHIBITORS; ENERGETICS; STRATEGY; LIBRARY;

D O I：

10.1021/ml500388q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A direct binding screen of 100 000 sp(3)-rich molecules identified a single diastereomer of a macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). A comprehensive toolbox of biophysical methods was applied to validate the original hit and subsequent analogues and also established a binding mode competitive with NOXA BH3 peptide. X-ray crystallography of ligand bound to MCL1 reveals a remarkable ligand/protein shape complementarity that diverges from previously disclosed MCL1 inhibitor costructures.

引用

页码：1308 / 1312

页数：5

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