Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.
Keywords: ABTR, ABT-737 resistant; AML, Acute Myeloid Leukemia; AUCinf, area under curve extrapolated to time infinity; AUClast, area under curve until last observed timepoint; Apoptosis; BH3, Bcl-2 homology domain 3; Bcl-2 family; Bcl-2, B-cell lymphoma-2; CHX, Cycloheximide; CL, rate of plasma clearance; Cmax, maximal plasma concentration; EC50, Half maximal effective concentration; IRES, Internal ribosome entry site; LD50, median lethal dose; MTD, Maximal tolerated dose; Mcl-1; Mcl-1, Myeloid cell leukemia-1; NMR, Nuclear magnetic resonance; PARP, Poly (ADP-ribose) polymerase; SAR, Structure-activity relationship; T1/2, plasma half-life; Tmax, time to maximal plasma concentration; VD, Volume of distribution; i.p., Intraperitoneal; leukemia; lymphoma; maritoclax; multiple myeloma; pyoluteorin.