ULK1 inhibitor induces spindle microtubule disorganization and inhibits phosphorylation of Ser10 of histone H3.

Certain tumors are dependent on autophagy for survival; thus, the use of unc-51-like autophagy activating kinase (ULK) 1 inhibitors to block autophagy has the potential for tumor treatment. However, ULK1 inhibitors affect processes other than autophagy. Herein, we report that the ULK1 inhibitors SBI-0206965/MRT68921 not only inhibit phosphorylation of histone H3 (Ser10) and delay chromatin condensation but also induce spindle microtubule disorganization to form short and fragmented microtubule polymers. Although the delay in chromatin condensation also delayed mitotic entry, the disorganized microtubule polymers resulted in unsegregated chromosomes and polyploidy. Although the effect on mitotic entry was moderate, polyploidy formation was decreased in ULK1 knockout cells with or without ULK2 knockdown. In conclusion, it will be helpful to consider the roles of ULK1 inhibitors in mitotic dysregulation, as well as autophagy, when evaluating their antitumor efficacy.