Table 3.

Characteristics of the new BH3 mimetics ABT-199, BIM SAHB, MIM 1, and BAM7, and comparison with ABT-737/263

CompoundTypeApproachBH3-Only mimicryTargetsBindingActivityApoptosisObservations
ABT-737/263Small molecule capable of binding to the hydrophobic groove of BCL-XLHigh-throughput screening by SAR-NMRBAD-likeBCL-2, BCL-XL, BCL-WHigh affinityDisplacement of BAD and BIM from BCL-2BAX/BAK-dependent only when MCL-1 is absent or neutralizedIn vivo antitumor effects; Phase II clinical trials
ABT-199ABT-263 derivative capable of binding to the hydrophobic groove of BCL-2Design based on complex X-ray crystal structure-BCL-2High affinityDissociation of BIM/BCL-2 complexBAX/BAK-dependent in BCL-2-dependent tumor cellsIn vivo antitumor effects; Phase I clinical trial
BIM SAHBDerivative of the BIM BH3 helix (amino acids 146–166)SAHBBIM-like (pan-BH3-only)BCL-XL, BCL-W, MCL-1, A1High affinityDisruption of BAX/BCL-XL and BAK/MCL-1 complexesBAX/BAK-dependent even in ABT-737- resistant cells, but not in normal cellsIn vivo antitumor effects; BH3 sequence-specific effects
MIM 1Small molecule displacing the binding of MCL-1-SAHB to the hydrophobic groove of MCL-1aCompetitive binding high-throughput screeningNOXA-likeMCL-1Computational docking studiesaInhibition of MCL-1-suppressed BAX activationbBAX/BAK-dependent in MCL-1-dependent but not BCL-XL-dependent cells
BAM 7Small molecule displacing the binding of a BIM BH3 helix to the BAX trigger siteCompetitive binding high-throughput screeningActivator-likeBAXNMR analysisBAX activationBAX-dependent apoptosis in BAK-deficient cells
  • Abbreviations: BH3, BCL-2 homology domain 3; SAR-NMR, structure/activity relationship by nuclear magnetic resonance.

  • aMCL-1 SAHB interacts with the binding groove of MCL-1, as shown by X-ray crystallography structural studies (ref. 37).

  • bMCL-1 SAHB disrupts BAK/MCL-1 complex (ref. 37).