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.

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