Search

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML., (© 2024 Wiley‐VCH GmbH.)

Triple-negative breast cancer (TNBC) has been considered the most aggressive and mortal breast cancer. Thus far, it remains an important challenge to develop TNBC targeted therapy. As revealed from numerous recent studies, ANXA2 may be a potential target to treat TNBC. In the present study, a natural product 5α-epoxyalantolactone (5α-EAL) was discovered as an anti-breast cancer stem cells (BCSCs) lead compound. Furthermore, 5α-EAL was found to be able to notably suppress the function of ANXA2 by covalently targeting cysteine 9 (Cys9) of ANXA2. To the best of our knowledge, 5α-EAL was recognized as the first small molecule functional inhibitor of ANXA2. It could significantly inhibit the formation of the heterotetrameric complex of ANXA2 and S100A10, which is capable of transporting E-cadherin (E-Ca) to the membrane. The above findings may be used as a possible strategy to develop novel anti-TNBC therapies targeting ANXA2.

Cancer stem cells (CSCs) have been reported to be involved in tumorigenesis, tumor recurrence, cancer invasion, metastasis, and drug-resistance. Therefore, the development of drug molecules targeting CSCs has become an attractive therapeutic approach. However, the molecules which can selectively ablate CSCs are extremely rare. To explore the leading compounds targeting CSCs, 52 analogues of triterpenoic acids were synthesized in this study, whose biological activities were evaluated. On the basis of the results of tumorsphere assay, two compounds 48 and 51, derived from oleanolic acid, exhibited suppressive effect on elimination of different type of CSCs. Meanwhile, compounds 48 and 51 could significantly inhibit the growth of several tumors both in vitro and in vivo. Furthermore, treatment of cancer cells with both of two compounds would dramatically increase the level of ROS, which might eliminate the CSCs. Collectively, the leading compounds 48 and 51 were promising anti-CSCs agents that merited further validation as a novel class of chemotherapeutics.

Cancer stem cells (CSCs) are responsible for carcinogenesis, cancer progression, relapse, metastasis and drug resistance. Therefore, the development of drug molecules targeting CSCs plays a vital role in medicinal researching field. However, there are extremely rare molecules that selectively ablate CSCs. The research and development of drugs targeting CSCs is limited due to a lack of anti-CSCs lead compounds. In this study, an anti-CSCs lead compound 35b was discovered, which was derived from the natural chemical scaffold of Symplostatin 4. This compound exhibited a significantly suppressive effect on tumor growth both in vitro and in vivo. Additionally, 35b could significantly reduce the number of melanoma tumor spheres and decrease the percentage of ALDH + melanoma cells. Further mechanism study illustrated that compound 35b could eliminate the melanoma CSCs by efficiently blocking Wnt/β-catenin signaling pathway. Collectively, our findings would provide a novel chemical scaffold and alternative idea of molecular design for development of anti-CSCs drugs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)