Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)
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The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-X L inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
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Mcl-1 is a crucial anti-apoptotic member of Bcl-2 family that contributes significantly to development of various human cancers.
“Myeloid cell leukemia-1 (Mcl-1) is a crucial anti-apoptotic member of the Bcl-2 protein family that contributes significantly to the development of various human cancers.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [227]
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Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity
Bruncko, M., Wang, L., Sheppard, G. S., Phillips, D. C., Tahir, S. K., Xue, J., Erickson, S., Fidanze, S., Fry, E., Hasvold, L., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501258m · Cited by 164 · see citing works
Self-citationPhysiological and Pharmacological Control of BAK, BAX, and Beyond
Luna-Vargas, M. P. A., & Chipuk, J. E. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.07.002 · Cited by 142 · see citing works
From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
Papatzimas, J. W., Gorobets, E., Maity, R., Muniyat, M. I., MacCallum, J. L., Neri, P., Bahlis, N. J., & Derksen, D. J. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00455 · Cited by 103 · see citing works
Allosteric inhibition of antiapoptotic MCL-1
Lee, S., Wales, T. E., Escudero, S., Cohen, D. T., Luccarelli, J., Gallagher, C. G., Cohen, N. A., Huhn, A. J., Bird, G. H., Engen, J. R., et al. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3223 · Cited by 59 · see citing works
Anderson, G. R., Wardell, S. E., Cakir, M., Crawford, L., Leeds, J. C., Nussbaum, D. P., Shankar, P. S., Soderquist, R. S., Stein, E. M., Tingley, J. P., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aae0348 · Cited by 53 · see citing works
Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming
Conage‐Pough, J. E., & Boise, L. H. (2018) · The FEBS Journal · doi:10.1111/febs.14505 · Cited by 32 · see citing works
Therapeutics Targeting the Core Apoptotic Machinery
Hamilton, C., Fox, J. P., Longley, D. B., & Higgins, C. A. (2021) · Cancers · doi:10.3390/cancers13112618 · Cited by 26 · see citing works
- Authors
- Leverson, J. D., Zhang, H., Chen, J., Tahir, S. K., Phillips, D. C., Xue, J., Nimmer, P., Jin, S., Smith, M., Xiao, Y., Kovar, P., Tanaka, A., Bruncko, M., Sheppard, G. S., Wang, L., Gierke, S., Kategaya, L., Anderson, D. J., Wong, C., Eastham-Anderson, J., Ludlam, M. J. C., Sampath, D., Fairbrother, W. J., Wertz, I., Rosenberg, S. H., Tse, C., Elmore, S. W., & Souers, A. J.
- Affiliations
- AbbVie (United States) (US)
- Genentech (US)
- Corresponding author
- Leverson, J D
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2015-01-15
- Volume
- 6
- Issue
- 1
- Pages
- e1590-e1590
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC4669759
- OpenAlex
- W2059416155
- Cited by
- 440
- References
- 72
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 21 · 2023: 23 · 2022: 22 · 2021: 31 · 2020: 41 · 2019: 60 · 2018: 61 · 2017: 59 · 2016: 71 · 2015: 25
- FWCI
- 32.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Genentech
- Japan Society for the Promotion of Science (26860331)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- Mcl-1 inhibitors, indole-2-carboxylic acid, navitoclax, BCL-2 inhibitor, mitochondrial apoptosis, multiple myeloma, non-small cell lung cancer, drug synergy, BH3 profiling, protein-protein interaction inhibitors
- MeSH terms
- Bcl-2-Like Protein 11, Aniline Compounds, Carboxylic Acids, Cell Survival, Drug Synergism, Humans, Indoles, Membrane Proteins, Neoplasms, Proto-Oncogene Proteins, Sulfonamides, Apoptosis, Cell Line, Tumor, Apoptosis Regulatory Proteins, Small Molecule Libraries, Myeloid Cell Leukemia Sequence 1 Protein
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