Platinum
drugs are common in chemotherapy, but their clinical applications
have been limited due to drug resistance and severe toxic effects.
The combination of platinum drugs with other drugs with different
mechanisms of anticancer action, especially checkpoint inhibitors,
is increasingly popular. This combination is the leading strategy
to improve the therapeutic efficiency and minimize the side effects
of platinum drugs. In this review, we focus on the mechanistic basis
of the combinations of platinum-based drugs with other drugs to inspire
the development of more promising platinum-based combination regimens
in clinical trials as well as novel multitargeting platinum drugs
overcoming drug resistance and toxicities resulting from current platinum
drugs.
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.
Treatment of triple-negative breast cancer (TNBC) has
long been
a medical challenge because of the lack of effective therapeutic targets.
Targeting lipid, carbohydrate, and nucleotide metabolism pathways
has recently been proven as a promising option in view of three heterogeneous
metabolic-pathway-based TNBC subtypes. Here, we present a multimodal
anticancer platinum(II) complex, named Pt(II)caffeine, with a novel
mode of action involving simultaneous mitochondrial damage, inhibition
of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion
of autophagy. All these biological processes eventually result in
a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate
that Pt(II)caffeine, influencing cellular metabolism at multiple levels,
is a metallodrug with increased potential to overcome the metabolic
heterogeneity of TNBC.
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