title: 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).
abstract: 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-XL 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.
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Tahir
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Phillips
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xue
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: P
authors.initials: P
authors.lastname: Nimmer
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kovar
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bruncko
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Sheppard
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gierke
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: L
authors.initials: L
authors.lastname: Kategaya
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wong
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: J
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: M J C
authors.initials: MJ
authors.lastname: Ludlam
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: I
authors.initials: I
authors.lastname: Wertz
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tse
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Elmore
authors.affiliation: Oncology Development, AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Souers
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002264:Carboxylic Acids; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002264:Carboxylic Acids; D007211:Indoles; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D013449:Sulfonamides; C058980:indole-2-carboxylic acid; C528561:navitoclax