Fibroblast Activation Protein α Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity

Bufadienolides are the major pharmacologic
constituents of traditional
Chinese medicine Chan’su, which is frequently used clinically
for cancer treatment in China. Motivated by reducing or avoiding the
cardiac toxicity of bufadienolides, we have designed, synthesized,
and evaluated the fibroblast activation protein α (FAPα)
activated tripeptide arenobufagin prodrugs with the purpose of improving
the safety of arenobufagin (a representative bufadienolide). Among
these FAPα-activated prodrugs, 3f exhibited the
best hydrolytic efficiency by recombinant human FAPα (rhFAPα)
and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed
that there are nonapparent changes in echocardiography, pathological
section of cardiac muscle, and the lactate dehydrogenase activities
(LDH) in 3f-treatment tumor-bearing mice, even when the
dose reached 3 times the amount of parent drug arenobufagin that was
used. Compound 3f also exhibits significant antitumor
activity in vitro and in vivo. The improved safety profile and favorable
anticancer properties of 3f warrant further studies of
the potential clinical implications. Our study suggests that FAPα
prodrug strategy is an effective approach for successful increasing
the therapeutic window of bufadienolides.