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

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• 作者：Chao Fang ; Brendan D鈥橲ouza ; Christopher F. Thompson ; Matthew C. Clifton ; James W. Fairman ; Ben Fulroth ; Alison Leed ; Patrick McCarren ; Lili Wang ; Yikai Wang ; Clementine Feau ; Virendar K. Kaushik ; Michelle Palmer ; Guo Wei ; Todd R. Golub ; Brian K. Hubbard ; Michael H. Serrano-Wu
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1308-1312
• 全文大小：280K
• ISSN：1948-5875

文摘

A direct binding screen of 100鈥?00 sp³-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.
<h4>Keywords: h4> MCL1; myeloid cell leukemia 1; sp³-rich; biophysical validation