Rki-1447, A Potent Rock Inhibitor With Anti-Tumor And Anti-Invasive Activities In Breast Cancer

Rho-associated kinases 1 and 2 (ROCKs) are intimately involved in metastasis and this prompted the development of ROCK inhibitors (RKIs) as anti-metastatic agents. Here, we describe the development of RKI-1447 which inhibits ROCK 1 and 2 potently in vitro (IC 50 s; 14 and 6 nM, respectively) and suppresses the phosphorylation of ROCK substrates MLC2 and MYPT1 in human breast cancer cells (IC 50 ; 100 nM). The crystal structure of the RKI-1447-ROCK1 complex reveals that RKI-1447 binds the hinge region in the ATP binding site. RKI-1447 is highly selective and does not affect the phosphorylation levels of Akt, Erk, Mek and S6. RKI-1447 is also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PKA-meditated lamelipodia and filopodia formation following PDGF and bradykinin stimulation, respectively. RKI-1447 inhibits migration, invasion and anchorage-independent tumor growth of breast cancer cells. A structurally-related analog RKI-1313 that is inactive against ROCKs in vitro (IC 50 > 10 µM) has little effects on migration, invasion and anchorage-independent growth. Finally, RKI-1447 is highly effective at inhibiting the growth of ErbB2-driven breast tumors in a transgenic animal model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2942. doi:1538-7445.AM2012-2942