6-Aminoindole

Discover 4beta-NH-(6-aminoindole)-4-desoxy-podophyllotoxin with nanomolar-potency antitumor activity by improving the tubulin binding affinity on the basis of a potential binding site nearby colchicine domain.[Pubmed:30878833]

Eur J Med Chem. 2019 May 15;170:73-86.

The colchicine binding site of tubulin is an attractive molecular target domain for cancer therapies. However, there was no FDA approved drug for targeting colchicine domain. Our previous crystallography discovered that a potential binding site of alphaT5 loop-alphaH7 nearby colchicine domain was beneficial for introducing affinity fragment. In this work, benzo heterocycles (i.e., indole, indazole and quinoline) with the high affinity ability of alphaT5 loop-alphaH7 were chosen as affinity fragment to modify the molecule structure of podophyllotoxin for improving the tubulin binding affinity. 4beta-NH-(benzo heterocycles)-4-desoxy-podophyllotoxin were synchronously located at alpha/beta interface of tubulin through providing affinity fragment to alphaT5 loop-alphaH7 (i.e., alpha178Ser, alpha182Val, alpha241Phe) and colchicine domain (i.e., beta241Cys, beta124ASP). 4beta-NH-(6''-aminoindole)-4-desoxy-podophyllotoxin not only exhibited nanomolar antitumor potency in vitro but also destroyed solid tumor growth without lethal toxicity in vivo. The correctness of rational drug design was strictly demonstrated by bioactivity test.