An intravenous (i.v.) route-compatible formulation of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, improves FL118 antitumor efficacy and therapeutic index (TI).

We recently reported a novel anticancer small molecule, designated FL118, which was discovered via high throughput screening (HTS), and followed by hit-lead in vitro and in vivo analysis. FL118 selectively inhibits the expression of four major cancer survival-associated gene products (survivin, Mcl-1, XIAP, and cIAP2) and shows promising antitumor activity in animal models of human cancers when administered using a weekly x 4 schedule (Ling et al., PLOS ONE. 2012, 7: e45571). Here, we compared the antitumor efficacy and therapeutic index (TI) of FL118 in a newly developed Tween 80-free formulation that can be delivered intravenously (i.v.) and intraperitoneally (i.p.) against the previous Tween 80-containing formulation that can only be delivered via an i.p. route. We found that the maximum tolerated dose (MTD) for FL118 in the i.v. formulation increases 3-7 fold in comparison with the MTD of FL118 in the i.p. formulation. FL118 in the i.v. recipe was able to eliminate human tumor xenografts in all three major schedules tested (daily x 5, q2 x 5 and weekly x 5). In contrast, FL118 was able to eliminate human tumor xenografts in the i.p. formulation only with the weekly x 4 schedule previously reported. The TI of FL118 in the i.v. formulation reached 5-6 in the most effective schedule, while the TI of FL118 in the i.p. formulation was only 1.3 - 2. These findings overcome several clinical challenges including FL118 formulation to realize clinically compatible drug administration routes, and expanding effective treatment schedules. The striking improvement of the TI makes FL118 a much safer drug for further development toward clinical trials.