alisertib (MLN8237)

Collectively, our findings systematically reveal that Alisertib exerts significant AURKA-independent antitumor effects in colon cancer, likely mediated through alternative mechanisms such as the regulation of ZAP70 and associated immune pathways. This study provides a novel perspective on the pharmacological action of Alisertib and its clinical application.

Importantly, TCHP inhibition not only suppresses tumor growth directly but also sensitizes liver cancer cells to the AURKA inhibitor alisertib, allowing tumor suppression at reduced drug doses and mitigating toxicity risks. Collectively, our findings establish TCHP as a potential oncogenic driver and therapeutic vulnerability in liver cancer and highlight the TCHP-AURKA axis as a promising target for synergistic treatment strategies.

Across a panel of NB and prostate cancer lines, QW-5-70 maintained low-nanomolar activity and remained effective in vincristine-resistant BE2C/VCR and paclitaxel-resistant PC-3/TxR cells. Combination studies revealed a combination index (CI)-defined synergistic interactions at selected dose pairs with the ornithine decarboxylase inhibitor DFMO, and enhanced apoptotic and clonogenic suppression when combined with the Aurora A kinase inhibitor MLN8237. Collectively, QW-5-70 is a potent CBSI that circumvents P-gp-associated resistance, triggers mitotic arrest and apoptosis, and achieves significant antitumor activity in multidrug-resistant tumor models with acceptable tolerability, supporting its further preclinical development alone and in combination with other drugs.

These findings highlight the superiority of scL-ALI in overcoming delivery barriers and enhancing therapeutic efficacy of alisertib, while possibly minimizing undesirable side effects in normal tissues. The scL-ALI nanocomplex shows enhanced therapeutic potential for treating AURKA-driven malignancies, particularly in combination with radiation therapy.

P2, N=50, Not yet recruiting, Puma Biotechnology, Inc.

P1, N=24, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

P2, N=96, Completed, Mayo Clinic | Active, not recruiting --> Completed

The results demonstrated the potential of using cilia-promoting drugs, such as Alvocidib and Alisertib, to suppress cancer cell replication. Additionally, it shows the massive benefits of integrating accessible large language models to conduct sweeping, rapid, and accurate literature searches.

Our findings suggest that Res may regulate BCa cell expression through the AURKA/STAT3 axis, providing a theoretical foundation for the structural optimization of Res and the development of multi-target drugs for clinical application.

In vitro validation narrowed compounds of interest to raltitrexed, alisertib, GTX-007, LY315920, and PD0325901. Treatment with alisertib leads to decrease in H2AK119ub and shift in the immune tumor microenvironment. Alisertib efficacy in HGSC is dependent on functional CBX2 and cell target engagement confirms selectivity for CBX2, supporting that alisertib activity involves CBX2 inhibition.

In addition, we review the status of AURKA-specific inhibitors in clinical evaluation and their associated adverse effects. Finally, we cite the emerging therapeutic strategy of proteolysis targeting chimeras (PROTACs) as an innovative means to selectively degrade AURKs, offering a novel approach to targeted cancer therapy.

In this study, we report the development of CCT400028, a second-generation alisertib-derived Aurora A PROTAC...Potent Aurora A degradation was shown in three pediatric tumor cell lines, as well as excellent selectivity and on-target mechanism of action. CCT400028 and a matched inactive control analogue fulfill the criteria for a degrader chemical probe for studying Aurora A degradation in vitro.