Fig. 1: Summary of the structure-based design of macrocyclic MCL-1 inhibitor ABBV-467. | Communications Medicine

Fig. 1: Summary of the structure-based design of macrocyclic MCL-1 inhibitor ABBV-467.

From: Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

Fig. 1

a Structure of linear compound 1 (MIK665) and X-ray crystal structure of compound 1 in complex with MCL-1 (PDB 8EKX). b Magnified view of central binding pose of compound 1 complexed with MCL-1 reveals proximity within 3.9 Å and possible macrocyclization. c Design of macrocyclic prototype molecule 2 as inspired by folded binding pose of compound 1 and subsequent in silico-based design with appropriate energy-minimized macrocyclic constraints. d X-ray crystal structure of compound 2 in complex with MCL-1 (PDB 8EL0). e Multiparameter investigation led to generation of ABBV-467. f X-ray crystal structure of ABBV-467 in complex with MCL-1 (PDB 8EL1).

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