KINSIE DISPERSIO SERIES

Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Among these UC-112 analogs, 10f, 10h, 10k, 10n showed the most potent antiproliferative activities. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC-112 with an indole moiety was preferred to other moieties. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors.

KINSIE DISPERSIO SERIES

We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. Further clinical trials with these peptides are warranted to examine its effects on various types of cancer. This review describes the most recent advances and innovations in the use of CPPs in several types of cancer, highlighting their crucial importance for various purposes, from therapeutic to diagnosis. Usually, their clinical application is limited by its poor aqueous solubility, immunogenicity issues and dose-limiting toxicity. Furthermore, in preclinical tests, the anti-tumor efficacy of this peptide was evaluated on human breast cancer, prostate cancer, ovarian cancer, and melanoma cells in vitro, leading to high expression of p53 and promoting cell cycle arrest.Дespite the numerous in vitro and in vivo studies with promising results, and the increasing number of clinical trials using CPPs, few treatments reach the expected clinical efficacy. Other examples are CopA3, that selectively decreased the viability of gastric cancer cells, and the CPP p28. In other cancers, such as esophageal cancer, the attachment of Magainin 2 (MG2) to Bombesin (MG2B), another CPP, led to pronounced anticancer effects. These above-mentioned peptides, conjugated with traditional chemotherapeutic such as Doxorubicin (DOX) and Paclitaxel (PTX), have also been shown to induce apoptosis of breast and liver cancer cells, as well as in lung cancer cells, respectively. Some notable examples are TAT and Penetratin, capable of penetrating the central nervous system (CNS) and, therefore, acting in cancers of this system, such as Glioblastoma Multiforme (GBM). Cell-Penetrating Peptides (CPPs) are peptides that can transport into the cell a wide variety of biologically active conjugates (or cargoes), and are, therefore, promising in the treatment and in the diagnosis of several types of cancer. Cancer is the second leading cause of death in the world and its treatment is extremely challenging, mainly due to its complexity.

Kinsie dispersio