Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis.
Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.
Nguyen
Mai
M
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, QC, Canada.
Marcellus
Richard C
RC
Roulston
Anne
A
Watson
Mark
M
Serfass
Lucile
L
Murthy Madiraju
S R
SR
Goulet
Daniel
D
Viallet
Jean
J
Bélec
Laurent
L
Billot
Xavier
X
Acoca
Stephane
S
Purisima
Enrico
E
Wiegmans
Adrian
A
Cluse
Leonie
L
Johnstone
Ricky W
RW
Beauparlant
Pierre
P
Shore
Gordon C
GC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000069286:Bortezomib; C520962:obatoclax