ISA-2011B

ISA-2011B is a PIP5Kα inhibitor with promising anticancer effects .

Signaling Pathways >> Others >> Others

Research Areas >> Cancer

The proliferation rate of PC-3 cells after treatment with ISA-2011B at 10, 20, and 50 μM is significantly reduced to 58.77%, 48.65%, and 21.62% of vehicle-treated controls, respectively. ISA-2011B exhibits the highest binding affinity to PIP5K1α, and to MAP/microtubule affinity-regulating kinase 1 and 4 (MARK1 and MARK4) across 460 kinases. ISA-2011B treatment inhibits PIP5K1α expression by 78.6% in PC-3 cells[1]. ISA-2011B leads to a remarkable reduction in AR-V7 and CDK1 in both nucleus and cytoplasm of 22Rv1 cells. ISA-2011B treatment also abolishes AR expression in the nucleus, without depleting the cytoplasmic AR[2].

ISA-2011B significantly inhibits growth of tumor cells in xenograft mice, and is mediated by targeting PIP5K1α-associated PI3K/AKT and the downstream survival, proliferation, and invasion pathways[1]. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice[2].

Cells are grown in phenol red-free RPMI-1640 medium 24 hours and then are treated with drugs alone or in combination for 24 hours or 48 hours. Enzalutamide at 5 μM or ISA-2011B at 20 μM or 50 μM final concentrations or solvent DMSO 1% is used. For treatment of 22Rv1 cells with MG132, a proteasome inhibitor, cells are treated with MG132 at 1 μM. For combination treatment of MG132 and ISA-2011B, cells are pre-treated with MG132 for 30 min at 1 μM prior to treatment of ISA-2011B[2].

Mice: BALB/c nude mice aged 8 to 12 wk are used in the experiments. Tumor cells are implanted into the mice. Tumor xenografts are treated with vehicle (control), docetaxel (10 mg/kg), ISA-2011B (40 mg/kg), and docetaxel (10 mg/kg) in combination with ISA-2011B (40 mg/kg) every second day[1].

[1]. Semenas J, et al. The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer. Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3689-98.

[2]. Sarwar M, et al. Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells. Oncotarget. 2016 Sep 27;7(39):63065-63081.

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