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

Chao Fang; Brendan D'Souza; 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

doi:10.1021/ml500388q

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

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

Authors

Chao Fang¹, Brendan D'Souza¹, Christopher F Thompson¹, Matthew C Clifton², James W Fairman², Ben Fulroth¹, Alison Leed¹, Patrick McCarren¹, Lili Wang¹, Yikai Wang¹, Clementine Feau¹, Virendar K Kaushik¹, Michelle Palmer¹, Guo Wei¹, Todd R Golub³, Brian K Hubbard¹, Michael H Serrano-Wu¹

Affiliations

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.