Journal
Development of Covalent Small-Molecule Fluorescent Probes for DNA Methyltransferase 1 Detection in Cancer Cells and Cervical Exfoliated Cells
DNA methyltransferase 1 (DNMT1) overexpression is associated with aberrant methylation and tumorigenesis, making its detection vital for tumor diagnosis. In this study, RG108 derivatives bearing cysteine-targeted covalent moieties were constructed as warheads for the DNMT1 detectors. Following affinity assessment by surface plasmon resonance, warheads containing a 2-fluoroacrylamido moiety were selected for preparing fluorescein-labeled probes
Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer
Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2
Discovery of Novel 4,5-Dihydropyrrolo[3,4-c]pyrazol-6(2H)-one-Based Tubulin Inhibitors Targeting Colchicine Binding Site with Potent Anti-Ovarian Cancer Activity
To address the toxicity of current microtubule inhibitors, we employed the GeminiMol deep learning model to screen the Zinc20 database, identifying a novel 4,5-dihydropyrrolo[3,4-
Palladium(II)-Indenyl Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models
In this study, we synthesized novel Pd(II)-indenyl complexes using various
Discovery of Novel Azaphenothiazine Derivatives to Suppress Endometrial Cancer by Targeting GRP75 to Impair Its Interaction with IP3R and Mitochondrial Ca2+ Homeostasis
Endometrial cancer (EC) is the most common cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound
Design and Development of IKZF2 and CK1α Dual Degraders
Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound
Making Protein Degradation Visible: Discovery of Theranostic PROTACs for Detecting and Degrading NAMPT
Proteolysis-targeting chimera (PROTAC) is emerging as a promising technology in targeted protein degradation and drug discovery. However, there is still a lack of effective chemical tools to real-time detect and track the protein degradation. Herein, the first fluorescent and theranostic PROTACs were designed for imaging the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells. Compound
Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes
A new series of seven gold(I) complexes (
Novel Hybrids of 3-Substituted Coumarin and Phenylsulfonylfuroxan as Potent Antitumor Agents with Collateral Sensitivity against MCF-7/ADR
Twenty-three new coumarin-furoxan hybrids were synthesized, which exhibited nanomole antiproliferation activities in A2780, A2780/CDDP, MCF-7/ADR, and MDA-MB-231. Among them, compound
In Vitro and In Vivo Biological Activities of Dipicolinate Oxovanadium(IV) Complexes
The work is focused on anticancer properties of dipicolinate (dipic)-based vanadium(IV) complexes [VO(dipic)(N
Design, Synthesis, and Pharmacological Evaluation of Metabolically Stable Apelin Receptor Antagonists with Improved In Vivo Exposure and Efficacy in Ovarian Cancer
Mechanism of Inhibition of the MeTC7 Ligand That Covalently Binds to VDR To Reduce PD-L1 Expression
Cancer-associated overexpression of the Vitamin D Receptor (VDR) is associated with good or poor prognosis, depending on the cancer type and stage. Here, we show that VDR is overexpressed in ovarian malignant tissues and upregulates PD-L1 surface expression in tumor cells, enabling immune evasion by the tumors. MeTC7, a VDR antagonist, has demonstrated strong inhibition of PD-L1 expression in vitro and in vivo. Using structural mass spectrometry and biophysical methods, we showed that MeTC7 binds covalently to VDR in the canonical ligand-binding pocket. Using ligand excess, additional covalently bound molecules were observed. Hydrogen-deuterium exchange mass spectrometry revealed that MeTC7 binding prevents optimal folding of the C-terminal region of VDR and impacts H10, which is part of the dimerization interface. Overall, our findings highlight a new mechanism of action for a VDR antagonist ligand and provide support for the use of the MeTC7 antagonist to inhibit PD-L1 and block tumorigenesis.
Precision-Oriented Theophylline-Platinum(IV) Prodrugs: Eliciting Synthetic Lethality in BRCA1-Deficient Ovarian Cancer with Enhanced Efficacy and Reduced Toxicity In Vitro and In Vivo
Ovarian cancer (OC) is a lethal gynecologic malignancy with limited treatments. Platinum(II) drugs are commonly used but faced severe toxicities and resistance. This study developed theophylline-platinum(IV) prodrugs (
Copper(II) Complexes with 2,2′:6′,2″-Terpyridine Derivatives Displaying Dimeric Dichloro−μ–Bridged Crystal Structure: Biological Activities from 2D and 3D Tumor Spheroids to In Vivo Models
Eight 2,2':6',2″-terpyridines, substituted at the 4'-position with aromatic groups featuring variations in π-conjugation, ring size, heteroatoms, and methoxy groups, were employed to enhance the antiproliferative potential of [Cu
Self-Assembling Amphiphilic Peptides Target the VDAC1-Hexokinase-II Complex to Induce Apoptosis in Cervical Carcinoma Cells
VDAC1, an outer mitochondrial membrane protein overexpressed in cancers, regulates apoptosis by interacting with antiapoptotic proteins and releasing apoptotic factors. We investigate novel multiblock cationic peptide amphiphiles targeting the VDAC1-Hexokinase-II complex in the mitochondria of cervical carcinoma cells. Amphiphilic peptide variants were designed by modifying the C-terminus of VDAC1 fragment LP1 with a cationic hydrophilic segment and the N-terminus with a hydrophobic domain, enabling self-assembly into nanofiber-like structures at elevated concentrations. In HeLa cells, these peptides triggered mitochondrial-mediated apoptosis through a decrease of the mitochondrial membrane potential, cytochrome
Modulatory Role of Pantropic Cell Signaling Pathways in the Antimigratory and Antiproliferative Action of Triazole Chelated Iridium(III) Complexes in Cervical Cancer Cells
In the current study, the antimigratory and antiproliferative effect of three substituted triazole-chelated iridium(III) complexes Ir-TRN, Ir-TRH, and Ir-TRF were studied with special emphasis on modulation of P53 activity, a cell cycle regulator. ERK2/MAPK, another crucial cell signaling pathway protein, was also shown to play a crucial role in cell migration and proliferation. The complexes increase the ROS generation within the cell, further supporting apoptotic induction by exerting cellular oxidative stress. These metal complexes also affect ER stress by altering ERp29, an ER-resident chaperone, further inducing the process of apoptosis. The iridium(III) complexes restrict cervical cancer cell migration and proliferation by exerting pronounced effects as P53 activators and downregulation of ERK2/MAPK activity in cervical cancer cells. The underpinning mechanism of P53 and ERK2/MAPK activity in cervical cancer cells in the presence of iridium(III) complexes was studied in detail in this study, which paves the way for developing promising avenues for cancer therapeutics.
Evaluating Alkaline Phosphatase-Instructed Self-Assembly of d-Peptides for Selectively Inhibiting Ovarian Cancer Cells
Cancer is a major public health concern requiring novel treatment approaches. Enzyme-instructed self-assembly (EISA) provides a unique approach for selectively inhibiting cancer cells. However, the structure and activity correlation of EISA remains to be explored. This study investigates new EISA substrates of alkaline phosphatase (ALP) to hinder ovarian cancer cells. Analogues
Discovery of Ruthenium(II) Metallocompound and Olaparib Synergy for Cancer Combination Therapy
Synergistic drug combinations can extend the use of poly(ADP-ribose) polymerase inhibitors (PARPi) such as Olaparib to BRCA-proficient tumors and overcome acquired or de novo drug resistance. To identify new synergistic combinations for PARPi, we screened a "micro-library" comprising a mix of commercially available drugs and DNA-binding ruthenium(II) polypyridyl complexes (RPCs) for Olaparib synergy in BRCA-proficient triple-negative breast cancer cells. This identified three hits: the natural product Curcumin and two ruthenium(II)-rhenium(I) polypyridyl metallomacrocycles. All combinations identified were effective in BRCA-proficient breast cancer cells, including an Olaparib-resistant cell line, and spheroid models. Mechanistic studies indicated that synergy was achieved via DNA-damage enhancement and resultant apoptosis. Combinations showed low cytotoxicity toward non-malignant breast epithelial cells and low acute and developmental toxicity in zebrafish embryos. This work identifies RPC metallomacrocycles as a novel class of agents for cancer combination therapy and provides a proof of concept for the inclusion of metallocompounds within drug synergy screens.
Discovery of a Novel, Potent, Orally Active, and Safe Inhibitor Targeting Human Mitochondrial RNA Polymerase
High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound
NSAID–Au(I) Complexes Induce ROS-Driven DAMPs and Interpose Inflammation to Stimulate the Immune Response against Ovarian Cancer
Inflammation contributes to the development of ovarian cancer, and chemoresistance is a principal obstacle in ovarian cancer treatment. Herein, we designed and synthesized a series of gold(I) complexes derived from NSAIDs or their analogues. Among them, complex
Anti-Cancer and Radio-Sensitizing Properties of New Bimetallic (N-Heterocyclic Carbene)-Amine-Pt(II) Complexes
Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[
NIR-II Aza-BODIPY Dyes Bioconjugated to Monoclonal Antibody Trastuzumab for Selective Imaging of HER2-Positive Ovarian Cancer
Using fluorescence-guided surgery (FGS) to cytoreductive surgery helps achieving complete resection of microscopic ovarian tumors. The use of visible and NIR-I fluorophores has led to beneficial results in clinical trials; however, involving NIR-II dyes seems to outperform those benefits due to the deeper tissue imaging and higher signal/noise ratio attained within the NIR-II optical window. In this context, we developed NIR-II emitting dyes targeting human epidermal growth factor receptor 2 (HER2)-positive ovarian tumors by coupling water-soluble NIR-II aza-BODIPY dyes to the FDA-approved anti-HER2 antibody, namely, trastuzumab. These bioconjugated NIR-II-emitting dyes displayed a prolonged stability in serum and a maintained affinity toward HER2 in vitro. We obtained selective targeting of HER2 positive tumors (SKOV-3) in vivo, with a favorable tumor accumulation. We demonstrated the fluorescence properties and the specific HER2 binding of the bioconjugated dyes in vivo and thus their potential for NIR-II FGS in the cancer setting.
Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site
Herein, a series of quinazoline and heterocyclic fused pyrimidine analogues were designed and synthesized based on the X-ray co-crystal structure of lead compound
Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer
Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader (
General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation In Vivo
Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of
Folic Acid–Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting
Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.
Induction of Ferroptosis in Glioblastoma and Ovarian Cancers by a New Pyrrole Tubulin Assembly Inhibitor
We synthesized new aroyl diheterocyclic pyrrole (ARDHEP)
Structure–Activity Relationships of Silver(I)- and Gold(I)–NHC Complexes Reveal Distinctly Different Responses of Cisplatin-Resistant Ovarian Cancer to Bis-NHC–Gold(I) Derivatives
American Chemical Society (ACS)
0022-2623
