AIn previous blog, I described Alisertib as an orally available selective aurora A kinase inhibitor. Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Today, I’d like to introduce another aurora A kinase inhibitor LY3295668.

LY3295668 is an orally active compound with greater selectivity over AurB than any Aurora inhibitor reported to date. The study from Gong X verified that.

In the study, the authors carried out a series experiments both in vitro and in vivo.

In vitro, in diffenfent cancer cell lines, LY3295668 mostly sensitized RB1mut lung, breast and glioblastoma, and other RB1 mutant cancer cells. Likewise, LY3295668 activated apoptosis pathways much more strongly in Rb-null versus Rb+ lung and breast cancer cell lines. Additionally, LY3295668 is a highly specific Aurora-A kinase inhibitor, with Ki values of 0.8 nM and 1038 nM for AurA and AurB, respectively. LY3295668, a highly specific AurA inhibitor, can kill Rb-deficient cancer cells at doses that have minimal effects on normal cells.

Subsequently, in vivo, LY3295668, a selective AurA inhibitor, is distinguished by minimal toxicity to bone marrow. Besides, it leads to durable regression of RB1mut tumor xenografts with no obvious side effects.

To summary, LY3295668 is a promising clinical candidate with low toxicity.

Gong X, et al. Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene. Cancer Discov. 2019 Feb;9(2):248-263.