Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy

Abstract

Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/ C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform-selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A-selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition-associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including smallcell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A-selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

“…AKIs in preclinical studies In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668 [86], BPR1K0609S1 [81,82], LDD970 [83], MK-8745 [84,85], AKI603 [80] and CYC3 [79]. The detailed information is shown in Table 3.…”

Nuclear localisation of Aurora-A: its regulation and significance for Aurora-A functions in cancer

“…Indeed, all the Aurora-A inhibitors that have entered clinical trials act as ATP-competitors in the active site pocket, which is highly conserved among human kinases. Despite great efficacy (MLN8237 [ 80 ]), increased selectivity (LY3295668 [ 81 ]) and elevated potency (MK-5108 has an IC 50 of 0.064 nM [ 82 ]), the ATP-competitive inhibitors are well known for exhibiting high promiscuity [ 83 – 85 ]. To date, they have not met expectations raised in cellular studies.…”

The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53

“…Marked N-myc loss was observed with 24 hours of CD532 treatment in vitro , and CD532 treatment of a NBL xenograft confirmed N-myc loss [30] . Recently LY3295668, another AURKA inhibitor (AURKAi), showed similar phenotypic effects to Alisertib in preclinical cancer models and now is being assessed in children with relapsed/refractory NBL [NCT04106219] [31] . Its specific effects on MYCN have not yet been reported, but together these data suggest that clinically relevant AURKAi can have a N-myc-destabilizing effect.…”