Purine-Type Compounds Induce Microtubule Fragmentation and Lung Cancer Cell Death through Interaction with Katanin

Microtubule targeting agents (MTAs)
constitute a class of drugs
for cancer treatment. Despite many MTAs have been proven to significantly
improve the treatment outcomes of various malignancies, resistance
has usually occurred. By selection from a two million entry chemical
library based on the efficacy and safety, we identified purine-type
compounds that were active against lung small cell lung cancer (NSCLC).
The purine compound 5a (GRC0321) was an MTA with good
effects against NSCLC. Lung cancer cells H1975 treated with 5a could induce microtubule fragmentation, leading to G2/M
cell cycle arrest and intrinsic apoptosis. Compound 5a directly targeted katanin and regulated the severing activity of
katanin, which cut the cellular microtubules into short pieces and
activated c-Jun N-terminal kinases (JNK). The microtubule fragmenting
effect of 5a is a unique mechanism in MTAs. It might
overcome the resistance problems that most of the MTAs have faced.