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ACS Med Chem Lett. 2014 Nov 11;5(12):1308-12. doi: 10.1021/ml500388q. eCollection 2014 Dec 11.

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

Author information

1
Broad Institute , 415 Main Street, Cambridge, Massachusetts 02142, United States.
2
Beryllium , 3 Preston Court, Bedford, Massachusetts 01730, United States.
3
Broad Institute , 415 Main Street, Cambridge, Massachusetts 02142, United States ; Dana-Farber Cancer Institute and Howard Hughes Medical Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.

Abstract

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.

KEYWORDS:

MCL1; biophysical validation; myeloid cell leukemia 1; sp3-rich

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