Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain.
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.
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Gizem
G
Akçay
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Matthew A
MA
Belmonte
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Brian
B
Aquila
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Claudio
C
Chuaqui
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Alexander W
AW
Hird
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Michelle L
ML
Lamb
Discovery Sciences, AstraZeneca, Cambridge, Cambridgeshire, UK.
Philip B
PB
Rawlins
Discovery Sciences, AstraZeneca, Waltham, Massachusetts, USA.
Nancy
N
Su
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Sharon
S
Tentarelli
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Neil P
NP
Grimster
Oncology Innovative Medicines Unit, AstraZeneca, Waltham, Massachusetts, USA.
Qibin
Q
Su
D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D001897:Boronic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D008239:Lysine