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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of Aurora Kinase inhibitors have been reported, and examples include VX-680 (Tozasertib), ZM447439 (a chemical probe), Hesperadin, TAK-901, and AZD-1152 (Figure 4.28). Tozasertib was in clinical development in a joint program between Vertex Pharmaceuticals and Merck & Co. It is a potent inhibitor of all aurora kinases, including types A, B, and C, and has been shown to inhibit cell-cycle progression, induce apoptosis, and block tumor growth in a number of in vivo xenograft models including those based on leukemias and colon and pancreatic tumors. However, a clinical trial was suspended in 2007 due to an observed QT-prolongation cardiotoxicity. Similarly, AstraZeneca developed AZD-1152 (also known as barasertib), although development was halted at the Phase II stage. These agents are all administered intravenously and share Grade-3 neutropenia as the most serious dose-limiting side effect. Structures of some known inhibitors of the Aurora kinases.
Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets
Published in Expert Review of Anticancer Therapy, 2020
Paolo Chieffi, Marco De Martino, Francesco Esposito
This kinase phosphorylates the H3 histone at serine 10, regulating chromosome condensation, alignment, and segregation. Also, spindle checkpoint function and cytokinesis are controlled by Aurora B kinase [54]. Furthermore, centrosome amplification has been connected to aneuploidy of TGCTs as reported by several research works [54]. Notably, in GC1 and TCam-2 testis-derived cell lines, the cell growth rate is strongly reduced following the inhibition of Aurora B kinase activity [55]. Definitely, AZD1152, ZM447439, Hesperadin 8, and VX-680 are Aurora B inhibitors that have been tested [55,56]. In particular, AZD1152 was tested in an extensive panel of human cancer xenograft considerably preventing the growth of tumors. Importantly, AZD1152 and other Aurora B inhibitors (ZM2, ZM3, GSK1070916) which block the phosphorylation of H3 histone on serine 10 [56], then abolishing cell division, show a reversible neutropenia as a main side effect, and they are in early clinical evaluation [55].
A patent update on PDK1 inhibitors (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2019
Simona Sestito, Simona Rapposelli
These compounds are indicated for patients affected by RSK2-dependent or Akt independent solid tumor or hematological cancers, in a suitable pharmaceutical formulation, alone or in combination with other appropriate anticancer drugs able to exert a synergic or at least additive effect, including other PDK1 inhibitors. In particular, the authors, suggested the use of alkylating agents (e.g., chlorambucil, cyclophosphamide), antimetabolites (e.g., methotrexate), aurora kinase inhibitors (e.g., ZM447439, VX-680, AZD1152); purine and pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), cytarabine (Ara-C), gemcitabine), spindle poisons (e.g., vinblastine, paclitaxel), podophyllotoxins (e.g. irinotecan, topotecan), antibiotics (e.g., doxorubicin, daunorubicin), inorganic ions (e.g., platinum complexes such as cisplatin, carboplatin), hormones (e.g., tamoxifen, leuprolide, flutamide, and megestrol), topoisomerase II inhibitors, EGFR inhibitors (e.g., gefitinib), antibodies (e.g., bevacizumab, rituximab), and various targeted agents such as HDAC inhibitors (e.g. vorinostat), Bcl-2 inhibitors, VEGF inhibitors, and cyclin-dependent kinase (cdk) inhibitors [57] as second active chemotherapeutic anticancer agents to be used in the combination.
Construction and validation of an NAD + metabolism-related lncRNA signature for predicting the prognosis and immune landscape of acute myeloid leukemia
Published in Hematology, 2023
Yu Zhu, Jinli Jian, Yujie Niu, Xiaoxiao Yang, Yuancheng Guo, Long Zhao, Bei Liu
Considering the differences in immune-related functions between the HR and LR groups, we predicted the sensitivity of both groups to immunotherapy by the TIDE algorithm. The results showed that the HR group had higher TIDE points, suggesting that overall, the HR group may be less sensitive to immune checkpoint inhibitor therapy than the LR group (Figure 10B). We further analysed the correlation of risk scores with sensitivity to chemotherapy and targeted drugs (Figure S6). A significant correlation was found between drug sensitivity and the risk score. Specifically, the LR group was more sensitive to specific agents, such as CP466722, cytarabine, navitoclax, OSI-027, VX-680, and ZM-447439 (Figure S7).