Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity

Hydroxamic
acid group is one of the characteristic pharmacophores
of histone deacetylase (HDAC) inhibitors. But here, we discovered
a series of hydroxamic acid-based microtubule destabilizing agents
(MDAs), which were derived from shortening the length of the linker
in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative
activity of these MDAs depended on the presence of hydroxamic acid
groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability,
and potent antitumor activity in multidrug-resistant cell lines and
A2780/T xenograft model. More importantly, in the patient-derived
xenograft models of triple-negative breast cancer and osimertinib-resistant
non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous
administration of 12b could induce more than 70% tumor
inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve
as a potential MDA for further investigation.