Mcl-1 Inhibitor III, UMI-77

A cell-permeable hydroxynaphthalenylthioacetate that exhibits Mcl-1-selective affinity (K_i against 2 nM FITC-BID_79-99 binding = 490 nM/90 nM MCl-1 & 23.83 µM/60 nM Bcl-2; K_i against 1 nM FAM-BID_80-99 binding = 5.33 µM/4 nM A1/Bfl-1; K_i against 2 nM FAM-BID_80-99 binding = 8.19 µM/40 nM Bcl-w, 23.83 µM/60 nM Bcl-2, and 32.99 µM/50 nM Bcl-xL), effectively inhibiting Mcl-1 BH3-binding groove-mediated interactions with various binding partners, including Noxa, Bax, and Bak, by simultaneously targeting the groove′s h2 & h3 hydrophobic pockets. Shown to inhibit the proliferation of BxPC-3, Panc-1, and Capan-2 prostate cancer cultures (IC₅₀ = 3.4, 4.4, and 5.5 µM, respectively) via apoptosis induction, while being less potent toward MiaPaca and AsPC-1 lines (IC₅₀ = 12.5 and 16.1 µM, respectively) with high Bcl-xL and low Mcl-1/Bak expression and. Despite its moderate in vitro murine liver microsome stability (t_1/2 = 45 mins), daily i.v. injection (60 mg/kg; 5 d/wk) is reported to effectively suppress BxPC-3 tumor expansion in mice in vivo without apparent animal toxicity, although severe weight loss is observed among mice received higher daily MUI-77 i.v. dosage of 80 mg/kg.

A cell-permeable, bioavailable hydroxynaphthalenylthioacetate compound that selectively and reversibly binds to the BH3 binding groove of Mcl-1 (K_i = 490 nM) and antagonizes its function by disrupting the heterodimerization of Mcl-1/Bax (IC₅₀ = 1.43 µM) and Mcl-1/Bak in cells. Exhibits high selectivity over other members of the Bcl-2 family (K_i = 5.33, 8.19, 23.83, and 32.99 µM, for A1/Bfl-1, Bcl-w, Bcl-2, and Bcl-xL, respectively). Inhibits the growth of BxPC-3, Panc-1 cells, and Capan-2 cells (IC₅₀ = 3.4, 4.4, and 5.5 µM, respectively) by inducing intrinsic apoptosis as evidenced by cytochrome c release and caspase-3 activation. However, it does not induce apoptosis in normal cells. Blocks the growth of BxPC-3 xenograft in SCID mice (60 mg/kg i.v. for 5 days for 2 weeks) without any cytotoxic effects on surrounding normal tissue. Exhibits desirable microsomal stability (t_1/2 = 45 min. in murine models).

Cell permeable: yes

Primary Target
binds to the BH3 binding groove of Mcl-1

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Use only fresh DMSO for reconstitution.

Abulwerdi, F., et al. 2014. Mol. Cancer Ther.13, 565.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)