| SGI-1776 is a novel ATP competitive inhibitor of Pim kinases, which are a family of three vertebrate protein serine/ threonine kinases (Pim-1, -2, and -3) belonging to the CAMK (calmodulin-dependent protein kinase-related) group. SGI-1776 potently inhibits Pim1, Pim2 and Pim3 with IC50 values of 7, 363 and 69 nM, respectively. In addition, SGI-1776 also potently inhibits FLT3 and haploid germ cell-specific nuclear protein kinase (Haspin) with IC50 values of 44 and 34 nM. In the androgen-independent prostate cancer cell lines, 22Rv1, PC3, and C4-2B, the IC50 values of SGI-1776 are 2, 3, and 3 µM, respectively. The LNCaP cell line shows lower response to SGI-1776 with IC50 of 5 µM, followed by the DU145 (8 µM) and RWPE2-W99 (9 µM) cell lines, whereas LAPC-4 (>10 µM) cells exhibit a minimal response. In 22Rv1 and C4-2B cells, SGI-1776 (1-10 µM) reduces phospho-p21Thr145 and phosphorylated BadSer112 protein levels, whereas total p21 and Bad remain constant. In addition, treatment with SGI-1776 causes a G1 arrest in a dose-dependent manner, inhibiting the natural progression to S phase in 22Rv1 and C4-2B cells. SGI-1776 (1-7.5 µM) also causes a dose-dependent increase in caspase-3 activity levels in both C4-2B and 22Rv1 cells. Overexpression of recombinant Pim-1 markedly increases sensitivity of SGI-1776-mediated prostate cancer cell apoptosis and p21Cip1/WAF1 phosphorylation inhibition, reinforcing the specificity of SGI-1776. SGI1776 is able to reduce cell viability in a multidrug resistance 1 protein??ased taxane-refractory prostate cancer cell line. In addition, SGI-1776 treatment is able to resensitize chemoresistant cells to taxane-based therapies by inhibiting multidrug resistance 1 activity and inducing apoptosis.[1] In MV-4-11 cell line, SGI-1776 (0.1 µM) reduces phosphorylation of histone H3 at Ser10 to only about 20% of vehicle control. c-Myc(Ser62) phosphorylation is decreased by about 50% relative to control at 0.1 µM SGI-1776, which is further reduced by 80% with 1 µM. Besides, SGI-1776 at the concentration of 1 and 10 µM inhibits RNA synthesis to about 80% and 50% of control in OCI-AML-3, respectively. In MV-4-11 xenografts model, tumors in the 75 mg/kg and 200 mg/kg SGI-1776 treatment groups disappear or become almost impalpable within 1 week after treatment. On day 22, 8 of 9 mice treated with 75 mg/kg SGI-1776 and all 10 mice treated with 200 mg/kg SGI-1776 experience a complete regression of their tumors. Moreover, 50 mg/kg SGI-1776 treated group has a significant 13% treated/control (T/C) and 100 mg/kg SGI-1776 treated group has 11% T/C on day 22.[2] |
