554723  ATRA-BA Hybrid

4-(Butanoyloxymethyl)phenyl-(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate, VNLG/124

The differentiation-inducer all-trans-Retinoic Acid (ATRA; Cat. No. 554720) and the histone deacetylase inhibitor (HDI) Butyric Acid (BA; Cat. No. 567430) are incorporated chemically via a benzyl ester linkage into a single more permeant mutual prodrug (MP) to facilitate their cellular uptake and to better synergize their cancer killing potency. The growth inhibitions of PC-3 and MDA-MB-231 by the MP (IC₅₀ = 1.02 and 0.01 µM, respectively) are much superior to those achieved by separate (IC₅₀ = 7.6 and 10.85 µM, respectively, with ATRA; IC₅₀ = 72.44 and >1000 µM, respectively, with BA) or combined dosing of ATRA/BA (55% vs. 30% PC-3 growth inhibition by 10 µM MP vs. co-treatment of 10 µM each of ATRA & BA). At 37°C, VNLG/124 is completely converted to ATRA and BA within an hour in fresh murine plasma, but is otherwise stable for more than 24 hours in the absence of esterase activity in 20 mM PBS.