Marinopyrrole A 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^[1]. Marinopyrrole A shows activity against all tested S. aureus strains, including glycopeptide-intermediate and vancomycin-resistant MRSA, and has potent activities against other Gram-positive organisms. In addition, marinopyrrole A is active against H. influenzae but is inactive against other tested Gram-negative strains. Marinopyrrole A displays substantial concentration-dependent killing against MRSA strain TCH1516 and is far more rapid in its antibiotic action than either vancomycin or linezolid. Marinopyrrole A exhibits a favorable therapeutic index, with 50% inhibitory concentrations (IC₅₀) in excess of 20× above the MIC in each case: 32 to 64 μg/mL against HeLa cells and 8 to 32 μg/mL against L929 cells^[2]. 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^[3]. Marinopyrrole A is much more effective against Bcl-2-dependent RS4;11 cells (IC₅₀: 2 μM) when compared to Mcl-1-dependent HeLa cells (IC₅₀: 20 μM)^[4].

• [1]. Doi K, et al. 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. J Biol Chem. 2012 Mar 23;287(13):10224-35.

  [2]. Haste NM, et al. Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011 Jul;55(7):3305-12.

  [3]. Gomez-Bougie P, et al. The selectivity of Marinopyrrole A to induce apoptosis in MCL1high BCL2low expressing myeloma cells is related to its ability to impair protein translation. Br J Haematol. 2016 Aug 14.

  [4]. Eichhorn JM, et al. Purported Mcl-1 inhibitor marinopyrrole A fails to show selective cytotoxicity for Mcl-1-dependent cell lines. Cell Death Dis. 2013 Oct 24;4:e880.