Uses
Rigosertib is a microtubule destabilizing agent which may be employed in the treatment of high-?risk myelodysplastic syndrome.
Definition
ChEBI: Rigosertib is an N-[2-methoxy-5-({[2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)phenyl]glycine in which the double bond has E-configuration. It is a non-ATP-competitive inhibitor of PLK1 with an IC50 of 9 nM and exhibits anti-cancer properties. It has a role as a microtubule-destabilising agent, an EC 2.7.11.21 (polo kinase) inhibitor, an apoptosis inducer and an antineoplastic agent. It is a conjugate acid of a rigosertib(1-).
Biological Activity
rigosertib is a dual inhibitor of phosphoinositide 3-kinase (pi3k) and polo-like kinase 1 (plk1) [1].
in vitro
studies show that rigosertib inhibits the pi3k/akt pathway, down-regulates cyclin d1, induces noxa and bim and activates the jnk pathway in human leukemic cells. rigosertib induces apoptosis of a variety of human tumor cell lines including breast, prostate, ovarian, pancreatic, sclc, colorectal, melanoma and et al. for instant, it shows anti-tumor efficacy in bt20, mcf-7, bt474, ov-car-3, a549 and hct-116 with ic50 values of 80nm, 75nm, 50nm, 75nm, 90nm and 75nm, respectively. in addition, rigosertib is also effective against the drug resistant tumor cell lines. it potently inhibits tumor growth with ic50 values of 100nm and 50nm against mes-sa/dx5 and cem/c2, respectively. moreover, it is reported that rigosertib can affect the cell cycle of both normal cells and tumor cells. rigosertib leads to a blockade of cell cycle progression in the g1 and g2/m phases in normal diploid human fetal lung cells. when treated with du145 cells, rigosertib induces cell cycle arrest in g2/m phase [2].
in vivo
Rigosertib (250 mg/kg, i.p.) markedly inhibits tumor growth in mouse xenograft models of Bel-7402, MCF-7, and MIA-PaCa cells[3]. Rigosertib (200 mg/kg, i.p.) shows inhibition on tumor growth in a mouse xengraft model of BT20 cells[4].
IC 50
PLK1: 9 nM (IC50); PLK2: 260 nM (IC50); PDGFR: 18 nM (IC50); Src: 155 nM (IC50); BCR-ABL: 32 nM (IC50); Cdk1: 260 nM (IC50); Flt1: 42 nM (IC50); Fyn: 182 nM (IC50)
References
[1] anderson r t, keysar s b, bowles d w, et al. the dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas. molecular cancer therapeutics, 2013, 12(10): 1994-2005.
[2] reddy m v r, venkatapuram p, mallireddigari m r, et al. discovery of a clinical stage multi-kinase inhibitor sodium (e)-2-{2-methoxy-5-[(2′, 4′, 6′-trimethoxystyrylsulfonyl) methyl] phenylamino} acetate (on 01910. na): synthesis, structure–activity relationship, and biological activity. journal of medicinal chemistry, 2011, 54(18): 6254-6276.
