Polypharmacology
is a promising paradigm in modern drug discovery.
Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors
in which the hydroxamic acid moiety as the zinc binding functional
group was introduced to a quinazoline-based PI3K pharmacophore through
an appropriate linker. Systematic structure–activity relationship
studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies
and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression
of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis
in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show
significant in vivo anticancer efficacies with tumor growth inhibitions
of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall,
this work shows promise in discovering new anticancer therapeutics
by the approach of simultaneously targeting PI3K and HDAC pathways
with a single molecule.
Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.
Aberrant
activation of the PI3K pathway has been intensively targeted
for cancer therapeutics for decades, leading to more than 40 PI3K
inhibitors advanced into clinical trials. However, it is increasingly
noticed that PI3K inhibitors often showed limited efficacy as well
as a number of serious on-target adverse effects during the clinical
development. In this work, we designed and synthesized a novel photocaged
PI3K inhibitor 1, which could be readily activated by
UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated
remarkably enhanced antiproliferative activity against multiple cancer
cell lines and significant efficacy in the patient-derived tumor organoid
model. Furthermore, 1 also showed favorable anticancer
activity in an in vivo zebrafish xenograft model.
Taken together, the photocaged PI3K inhibitor 1 represents
a promising avenue for novel therapeutics toward precise cancer treatment.
Stimuli-responsive nanocarriers have been limited for bench-to-bedside translation mainly because the stimuli sensitivity and responsive rate are not high enough to ensure sufficient drug concentration at the target sites for superior therapeutic benefits. Herein, we reported an enhanced bioreduction-responsive and biodegradable nanocarrier based on the amphiphilic poly(ester urethane) copolymers (PAUR-SeSe) bearing multiple diselenide groups on the backbone. The copolymer could spontaneously self-assemble into stable micelles in aqueous medium with an average diameter of 68 nm, which could be rapidly disassembled in a reductive environment as a result of the reduction-triggered cleavage of diselenide groups. Furthermore, the PAUR-SeSe micelles showed an enhanced drug release profile and cellular uptake compared with the disulfide-containing analogue (PAUR-SS). CCK8 assays revealed that the antitumor activity of DOX-loaded PAUR-SeSe micelles was much higher than that of DOX-loaded PAUR-SS micelles. Besides, the blank micelles and degradation products were nontoxic up to a tested concentration of 50 μg mL. Therefore, the enhanced therapeutic efficacy and good biocompatibility demonstrated that this drug nanocarrier had great potential for smart antitumor drug delivery applications.
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