The immunomodulatory benzodiazepine Bz-423 inhibits B-cell proliferation by targeting c-myc protein for rapid and specific degradation.
Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F(1)F(o)-ATPase. Bz-423 inhibits F(1)F(o)-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful.
Sundberg
Thomas B
TB
Department of Chemistry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Ney
Gina M
GM
Subramanian
Chitra
C
Opipari
Anthony W
AW
Glick
Gary D
GD
D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D015317:Biogenic Polyamines; D018797:Cell Cycle Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D013481:Superoxides; D001569:Benzodiazepines; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases; C468549:Bz-423