A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

“…21 It also effectively inhibited survivin homodimerization, induced its degradation via the proteasome, and induced spontaneous apoptosis as expected. 21 Furthermore, compounds 82 to 86 may be subject to redox activation due to the iminoquinone moiety. Thus, cautions should be practiced when further evaluating these compounds.…”

“…As shown in Figure B, several 81 analogs, 82 (LQZ-7A), 83 (LQZ-7B), 84 (LQZ-7C), 85 (LQZ-7D), 86 (LQZ-7E), and 7 (LQZ-7F), were also identified from the chemical library that had different activities in targeting survivin and inducing spontaneous apoptosis in prostate cancer cell lines (Table ). Further medicinal chemistry study to optimize these inhibitors has also been attempted, leading to the identification of the two novel survivin inhibitors 8 (7F1, Figure B) and 9 (LQZ-7I, Figure C) that are very active in inducing survivin degradation, suppressing proliferation and inducing the spontaneous apoptosis of CRPC cells. − …”

“… These inhibitors have also been shown to induce spontaneous apoptosis of prostate and other cancer cell lines and synergize with docetaxel in prostate cancer cells (Table ). − However, only 7 and 9 have been tested in vivo where, at 25 mg/kg (every 3 days for eight treatments, IP) and 100 mg/kg (every other day for ten treatments, oral), respectively, and they both significantly inhibited the growth of PC-3 xenograft tumors without any obvious toxicity (Table ). , However, the pharmacokinetics of these compounds have not been studied.…”

“…Indeed, 7 with a hydrophilic tail is more soluble than 8 , and it was successfully administered via IP injection and validated to be effective in the prostate cancer cell PC-3 xenograft model . However, 8 was not studied in vivo due to low solubility . Thus, structural modifications of 8 to increase its solubility while maintaining its potency is desirable.…”

Toad venom-derived bufadienolides and their therapeutic application in prostate cancers: Current status and future directions

“…The first one is the high prevalence since it’s one of the leading cancers in men and one of the leading causes of deaths among men worldwide ( Gomella, 2017 ; Schatten, 2018 ; Zhang et al, 2022a ). The second characteristic is the high incidence of drug resistance, since more than 90% of PCa will eventually develop resistance to androgen-depredation therapy (ADT), termed as castration-resistant PCa (CRPC), and later second resistance to subsequent chemotherapies ( Armstrong and Gao, 2015 ; Cohen et al, 2021 ; Liotti et al, 2021 ; Morel et al, 2021 ; Ji et al, 2022 ; Peery et al, 2022 ). It’s known that various factors contribute to the development of drug resistance in PCa, such as the alteration/mutation of androgen receptor (AR) or oncogenes, metabolism adaptation, overexpression of ATP-binding cassette (ABC) transporters, apoptosis resistance, enhanced DNA repair and cellular defensive systems against toxic inducers, etc.…”