Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

Journal name:
Nature Chemical Biology
Year published:
Published online


Targeted covalent inhibition of disease-associated proteins has become a powerful methodology in the field of drug discovery, leading to the approval of new therapeutics. Nevertheless, current approaches are often limited owing to their reliance on a cysteine residue to generate the covalent linkage. Here we used aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain, and generated to our knowledge the first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies. These covalent binders exhibited improved potency in comparison to noncovalent congeners, as demonstrated in biochemical and cell-based assays. We identified Lys234 as the residue involved in covalent modification, via point mutation. The covalent binders discovered in this study will serve as useful starting points for the development of Mcl-1 therapeutics and probes to interrogate Mcl-1-dependent biological phenomena.

At a glance


  1. Structure-based design of new covalent Mcl-1 inhibitors targeting Lys234.
    Figure 1: Structure-based design of new covalent Mcl-1 inhibitors targeting Lys234.

    (a) Structure of 4. (b) Docked structure of inhibitor 5 (yellow), illustrating the feasibility of targeting Lys234 using an aryl boronic acid carbonyl warhead.

  2. Covalent compounds selectively induced apoptosis in Mcl-1-dependent cell lines.
    Figure 2: Covalent compounds selectively induced apoptosis in Mcl-1-dependent cell lines.

    (a,b) Caspase-3/7 activity measured after a 2-h incubation with compounds 5 (a) and 11 (b) in Mcl-1-dependent multiple myeloma cells lines (blue), and in Mcl-1 independent cell lines (black). Experiments were run as duplicates.

  3. Activity of compound 11, but not staurosporine, required Bak.
    Figure 3: Activity of compound 11, but not staurosporine, required Bak.

    (a) Knockdown of Bak protein in NCI-H23 cells assessed by immunoblot after 72 h. Full gel images are in Supplementary Figure 2. (b,c) Caspase-3/7 activity in NCI-H23 cells treated with siRNA targeting Bak mRNA for 72 h before treatment with compound 11 (b) or staurosporine (c) for 6 h. Experiments were run as duplicates.

  4. Compound 5 disrupted Mcl-1 complexes in MOLP-8 cells at concentrations that induced apoptosis.
    Figure 4: Compound 5 disrupted Mcl-1 complexes in MOLP-8 cells at concentrations that induced apoptosis.

    (a) Immunoprecipitation (IP) of Mcl-1 from lysates of MOLP-8 cells treated with tenfold serial dilutions of compound 5 for 30 min, followed by immunoblot analysis. (b) Analysis of total protein amounts for Mcl-1 or Bak in lysates of cells treated as in a. Full gel images are in Supplementary Figure 3.

  5. Effect of Lys234 mutation on the biochemical potency.
    Figure 5: Effect of Lys234 mutation on the biochemical potency.

    (a,b) Inhibition of wild-type Mcl-1 and Mcl-1 Lys234 by compound 8 (a) and 6 (b). IC50 measurements were obtained by TR-FRET-based binding assay. Experiments were run as duplicates.


27 compounds View all compounds
  1. 2-formylphenylboronic acid
    Compound 1 2-formylphenylboronic acid
  2. 2-acetylphenylboronic acid
    Compound 2 2-acetylphenylboronic acid
  3. (S)-2-acetamido-6-amino-N-methylhexanamide
    Compound 3 (S)-2-acetamido-6-amino-N-methylhexanamide
  4. 3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 4 3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  5. 7-(3-((4-borono-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 5 7-(3-((4-borono-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  6. 7-(3-((3-acetyl-4-boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 6 7-(3-((3-acetyl-4-boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  7. 7-(3-((3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 7 7-(3-((3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  8. 7-(3-((3-acetylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 8 7-(3-((3-acetylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  9. 7-(3-((4-boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 9 7-(3-((4-boronophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  10. 7-(1,5-dimethyl-3-(phenoxymethyl)-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 10 7-(1,5-dimethyl-3-(phenoxymethyl)-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  11. 7-(3-((4-borono-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 11 7-(3-((4-borono-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  12. 7-(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 12 7-(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)-1-(2-morpholinoethyl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  13. 2-formyl-4-methoxyphenylboronic acid
    Compound 13 2-formyl-4-methoxyphenylboronic acid
  14. (S,E)-2-((5-acetamido-6-(methylamino)-6-oxohexylimino)methyl)phenylboronic acid
    Compound 14 (S,E)-2-((5-acetamido-6-(methylamino)-6-oxohexylimino)methyl)phenylboronic acid
  15. (S,E)-2-(1-(5-acetamido-6-(methylamino)-6-oxohexylimino)ethyl)phenylboronic acid
    Compound 15 (S,E)-2-(1-(5-acetamido-6-(methylamino)-6-oxohexylimino)ethyl)phenylboronic acid
  16. ethyl 7-(3-(chloromethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 16 ethyl 7-(3-(chloromethyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  17. ethyl 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 17 ethyl 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  18. 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 18 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  19. 7-(3-((3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 19 7-(3-((3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  20. ethyl 7-(3-((3-acetyl-4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 20 ethyl 7-(3-((3-acetyl-4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  21. 7-(3-((3-acetyl-4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 21 7-(3-((3-acetyl-4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  22. ethyl 7-(3-((3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 22 ethyl 7-(3-((3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  23. ethyl 7-(3-((3-acetylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 23 ethyl 7-(3-((3-acetylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  24. ethyl 7-(3-((4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 24 ethyl 7-(3-((4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  25. 7-(3-((4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 25 7-(3-((4-bromophenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
  26. methyl 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
    Compound 26 methyl 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate
  27. 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid
    Compound 27 7-(3-((4-bromo-3-formylphenoxy)methyl)-1,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylic acid

Accession codes

Referenced accessions

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Author information


  1. Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.

    • Gizem Akçay,
    • Matthew A Belmonte,
    • Brian Aquila,
    • Claudio Chuaqui,
    • Alexander W Hird,
    • Michelle L Lamb,
    • Sharon Tentarelli,
    • Neil P Grimster &
    • Qibin Su
  2. Discovery Sciences, AstraZeneca, Cambridge, Cambridgeshire, UK.

    • Philip B Rawlins
  3. Discovery Sciences, AstraZeneca, Waltham, Massachusetts, USA.

    • Nancy Su


G.A., N.P.G., B.A., C.C., A.W.H., M.L.L. and Q.S. designed the covalent inhibitors; G.A. and N.P.G. synthesized all compounds; G.A., M.A.B., P.B.R. and N.S. performed biological experiments. G.A., N.P.G., C.C., M.A.B., P.B.R., M.L.L., A.W.H., B.A., N.S., S.T. and Q.S. interpreted and discussed the results. G.A. and N.P.G. wrote the manuscript. All authors contributed to editing of the manuscript.

Competing financial interests

All authors are current or former employees of AstraZeneca Pharmaceuticals.

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    Supplementary Results, Supplementary Figures 1–11 and Supplementary Tables 1–4.

  2. Supplementary Note (869 KB)

    Synthetic Procedures

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