CG-1521

CG-1521: Treatment for Refractory Prostate Cancer

CG-1521 (aka JW-1521) (7-phenyl-2, 4, 6-hepta-trienoyl hydroxamic acid) is an inhibitor of histone deacetylase (HDAC) in the final stages of pre-clinical development. The compound has been shown to inhibit cell proliferation of both solid and hematological cancer cells and has been extensively studied in neuroblastoma and prostate cancer models.

Studies in prostate tumor cell lines show its distinct effects on cellular processes related to programmed cell death. Increased expression of cell cycle regulatory proteins including the mitotic kinase p34cdc and the cyclin dependent kinase inhibitor p21 were observed in LNCaP cells treated with CG-1521 and was accompanied by apoptosis. Bcl-2 protein levels were reduced. CG-1521 treatment stabilizes acetylated p53 with a concurrent increase in the endogenous levels of total p53. A gradual increase in p21 levels is also found which may be responsible for the cell cycle arrest.

CG-1521 stabilizes the acetylation of p53 (at Lys373 but not Lys320 or Lys 382) and increases levels of p53 in LNCaP cells. This is very different from the other HDAC inhibitors such as trichostatin, which stabilize the acetylation of p53 at Lys 382 but not Lys 373 or 320 and SAHA which does not appear to affect the acetylation of any of the lysine residues in the C-terminal domain of the protein.

When CG-1521 was combined with the anti-androgen bicalutamide (Casodex®), which is used clinically in the treatment of hormone responsive prostate cancer, an additive effect on growth inhibition and apoptosis in AR+ prostate cancer cells was found. Also, the combination treatment of AR- cells with CG-1521 and bicalutamide had a synergistic effect on growth inhibition; suggesting that CG-1521 may sensitize AR- prostate cancer cells to bicalutamide which would otherwise be unresponsive to hormone therapy.

CG-1521 is being developed as a treatment for both hormone responsive and refractory prostate cancer.

More information on CG-1521 – click here

REFERENCES

* Wiech, N., Lan-Hargest, H., Lea, M., Jung, M., Welsh, J.E., Helquist, K., Tenniswood, M., Packman, K.E., and Jeffrey, R. 2002. Characterization of the activity of the histone deacetylase inhibitor JW 1521 in solid tumor models. Proc .Amer.Assoc.Cancer Res. 43: (Abstr.)

* Roy, S., Packman, K., Jeffrey, R., and Tenniswood, M. 2005. Histone deacetylase inhibitors differentially stabilize acetylated p53 and induce cell cycle arrest or apoptosis in prostate cancer cells. Cell Death Differ. 00:1-10.

* de Ruijter, A.J.M., Kemp, S., Kramer, S., Meinsma, R.J., Kaufman, J.O., Caron, H., and van Kuilenburg, A.B.P. 2004. The novel histone deacetylase inhibitor BL 1521 inhibits proliferation and induces apoptosis in neuroblastoma cells. Biochem. Pharmacol. 68:1279-1288.

* Ouwehand, K., de Ruijter, A. J. M., van Bree, C., Caron, H., and van Kuilenburg, A. B. P. Histone deacetylase inhibitor BL 1521 induces a G1-phase arrest in neuroblastoma cells through altered expression of cell cycle proteins. FEBS Lett. 579, 1523-1528. 2005.

* Wang , D.-F., Wiest ,O., Helquist, P., Lan-Hargest, H., and Wiech, N.L. 2004. QSAR studies of PC-3 cell line inhibition activity of TSA and SAHA-like hydroxamic acids. Bioorg. Med. Chem. Lett. 13:707-711.

* Wang, D.-F., Wiest, O., Helquist, P., Lan-Hargest, H., and Wiech, N.L. 2004. On the function of the 14├ů long internal cavity of histone deacetylase inhibitors. J. Med. Chem. 47:3409-3417.

* Wiest, O., Wang, D.-F., Helquist, P., Tenniswood, M., Roy, S., and Wiech, N. L. Computer-aided molecular design of HDAC inhibitors. 2005. 229th National ACS Meeting, San Diego, CA March 13-17, 2005 (MEDI394, invited plenary talk).