Marinopyrrole A (Maritoclax) is a novel and specific Mcl-1 inhibitor with an IC50 value of 10.1 μM, and shows >8 fold selectivity than BCL-xl (IC50 > 80 μM). Maritoclax blocks the binding of Bim BH3 α-helix to Mcl-1 but not Bcl-XL. Maritoclax markedly inhibits the viability of Mcl-1-IRES-BimEL cells (EC50=1.6 μM) with a selectivity greater than 40-fold over Bcl-2-IRES-BimEL (EC50=65.1 μM) and Bcl-XL-IRES-BimEL (EC50=70.0 μM) cells. Maritoclax induces cell death selectively in Mcl-1-dependent but not Bcl-2- or Bcl-XL-dependent leukemia cells. Maritoclax induces proteasome-mediated Mcl-1 degradation without induction of Mcl-1 phosphorylation and Noxa expression. Maritoclax inhibits Mcl-1 interaction with Bim in intact cells and triggers cytochrome c release from isolated mitochondria. Maritoclax synergistically sensitizes lymphoma/leukemia cells to ABT-737. Marinopyrrole A (3 μM) induced-cell death is associated with MCL1 decrease and translation inhibition. Marinopyrrole A induces a dephosphorylation of EIF4EBP1 concomitant to a decrease of EIF4E phosphorylation.
In vivo, Maritoclax administration at 20 mg/kg/d intraperitoneally causes significant U937 tumor shrinkage, as well as 36% tumors remission rate in athymic nude mice, without apparent toxicity to healthy tissue or circulating blood cells.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 45 mg/mL|
 Doi K, et al. J Biol Chem. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation.
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