title: The vascular disrupting agent STA-9584 exhibits potent antitumor activity by selectively targeting microvasculature at both the center and periphery of tumors.
abstract: Vascular disrupting agents (VDAs) are an emerging class of therapeutics targeting the existing vascular network of solid tumors. However, their clinical progression has been hampered because of limited single-agent efficacy, primarily caused by the persistence of surviving cells at the well perfused "viable rim" of tumors, which allows rapid tumor regrowth to occur. In addition, off-target adverse events, including cardiovascular toxicities, underscore a need for compounds with improved safety profiles. Here, we characterize the mechanism of action, antitumor efficacy, and cardiovascular safety profile of (S)-2-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide hydrochloride (STA-9584), a novel tubulin-binding VDA. In vitro, 2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)aniline (STA-9122) (active metabolite of STA-9584) displayed increased potency relative to other tubulin-binding agents and was highly cytotoxic to tumor cells. STA-9584 induced significant tumor regressions in prostate and breast xenograft models in vivo and, in an aggressive syngeneic model, demonstrated superior tumor growth inhibition and a positive therapeutic index relative to combretastatin A-4 phosphate (CA4P). It is noteworthy that histological analysis revealed that STA-9584 disrupted microvasculature at both the center and periphery of tumors. Compared with CA4P, STA-9584 induced a 73% increase in central necrotic area, 77% decrease in microvasculature, and 7-fold increase in tumor cell apoptosis in the remaining viable rim 24 h post-treatment. Ultrasound imaging confirmed that STA-9584 rapidly and efficiently blocked blood flow in highly perfused tumor regions. Moreover, cardiovascular effects were evaluated in the Langendorff assay and telemetered dogs, and cardiovascular toxicity was not predicted to be dose-limiting. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new therapeutic VDA candidate.
authors: Synta Pharmaceuticals Corp., 125 Hartwell Avenue, Lexington, MA 02421, USA.
authors: Kevin P
authors: KP
authors: Foley
authors: Dan
authors: D
authors: Zhou
authors: Chris
authors: C
authors: Borella
authors: Yaming
authors: Y
authors: Wu
authors: Mei
authors: M
authors: Zhang
authors: Jun
authors: J
authors: Jiang
authors: Hao
authors: H
authors: Li
authors: Jim
authors: J
authors: Sang
authors: Tim
authors: T
authors: Korbut
authors: Josephine
authors: J
authors: Ye
authors: Xuemei
authors: X
authors: Zhang
authors: James
authors: J
authors: Barsoum
authors: Andrew J
authors: AJ
authors: Sonderfan
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001632:Bibenzyls / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008833:Microcirculation / Q000187:drug effects; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C577049:2-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D007555:Isoxazoles; D050257:Tubulin Modulators; D010649:Phenylalanine; C040105:combretastatin