Ideas for Novel MoA Molecules

A Novel Mode of Action

OSW-1 involves a novel mechanism of action that is independent of cell cycle and can even effectively kill dormant cancer cells (stem-like cancer cells) at sub-nM concentrations. Moreover, we discovered that OSW-1 abolishes the GRP78 survival pathway that is closely correlated with its cytotoxicity. GRP78 is a key member of the HSP70 protein family that functions as an ER chaperone involved in protein folding and assembly and ER-mediated stress signal. GRP78 is over-expressed in many cancers and plays important roles in tumor growth, tumor cell survival, angiogenesis, metastasis, drug resistance, and tumor immunity. Despite the fact that OSW-1 belongs to the saponins, it does not show any hemolytic tox-icity, even at 100μg/ml concentrations.

Mimaki Y, Kuroda M, Kameyama A, Sashida Y, Hirano T, Oka K, Maekawa R, Wada T, Sugita K, Beutler J A: Choles-tane glycosides with potent cytostatic activities on various tumor cells from Ornithogalum Saundersiae bulbs. Bioor-ganic Med. Chem. Lett. 1997; 7: 633. Zhou Y, Garcia-Prieto C, Carney DA., Xu RH, Pelicano, H, Kang Y, Yu W, Lou C, Kondo S, Liu J, Harris DM, Estrov Z, Keating MJ, Jin Z, Huang P. OSW-1: A natural compound with potent anticancer activity and novel mechanism of ac-tion. J. Natl. Cancer Inst. 2005; 97: 1781-1785 Garcia-Prieto C, Riaz Ahmed KB, Chen Z, Zhou Y, Hammoudi N, Kang Y, Lou C, Mei Y, Jin Z, Huang P.: Effective kill-ing of leukemia cells by the natural product OSW-1 through disruption of cellular calcium homeostasis. J. Biol. Chem. 2013; 288(5): 3240-50

Ideas for Novel MoA Molecules

>220 potential molecules are available

Alpha-Amanitin,

a bicyclic octapeptide

is known as a mycotoxin. Nowadays, reasearch showed also growth inhibition on androgen-dependent prostate carcinoma cells. (LNCaP and DU-145). abolishes the GPR78 survival pathway that is closely correlated with its cytoxtoxicity.

Inhibitor of RNA polymerase II (0.02 micrograms/ml). Moldenhauer G, Salnikov AV, Lüttgau S, Herr I, Anderl J, Faulstich H: Therapeutic potential of amanitin-conjugated anti-epithelial cell adhe-sion molecule monoclonal antibody against pancreatic carcinoma. J Natl Cancer Inst. 2012;104(8): 622-34.

OSW-1,

Garcia-Prieto C, Riaz Ahmed KB, Chen Z, Zhou Y, Hammoudi N, Kang Y, Lou C, Mei Y, Jin Z, Huang P. Effective killing of leukemia cells by the natural prod-uct OSW-1 through disruption of cellular calcium homeostasis. J. Biol. Chem. 2013; 288(5): 3240-50.

Verrucarin A

Liu Y, Gao X, Deeb D, Zhang Y, Shaw J, Valeriote FA, Gautam SC: J Exp Ther Oncol. 2016; 11(4): 251-260

Cyanobacteria, a new drug source with an unmatched novelty of bioactive natural products.