New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11488 - 11521

Published: July 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Language: Английский

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PROTACs: A novel strategy for cancer drug discovery and development

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Language: Английский

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Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 264, P. 115982 - 115982

Published: Nov. 25, 2023

Language: Английский

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Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin–Proteasome system

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116168 - 116168

Published: Feb. 1, 2024

Language: Английский

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Paeonol enhances a recombinant EGFR-targeted fusion protein-drug conjugate induced antitumor efficacy in esophageal cancer

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: 236, P. 116856 - 116856

Published: March 5, 2025

Language: Английский

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Nuclear PARP1‐Targeted Photosensitizer as a Dual‐Mode DNA‐Damaging Agent and Immune Activator for Tumor Ablation

Advanced Healthcare Materials, Journal Year: 2023, Volume and Issue: 12(31)

Published: Sept. 10, 2023

Photodynamic therapy is a promising cancer therapeutic method that can damage DNA via photoinduced reactive oxygen species production. However, tumor cells initiate repair pathways to resist oxidative damage. In this study, nuclear-targeted photosensitizer PARP-PS with poly (ADP-ribose) polymerase 1 (PARP1) inhibitory effect developed based on the reported PARP1 inhibitor, rucaparib. As dual-mode DNA-damaging agent, damages upon photoirradiation and enhances by blocking pathway inhibition degradation. Both in vitro vivo investigations demonstrate exhibits high antitumor activity few side effects breast cancer. addition, act as an immunogenic cell death inducer activate immune responses characterized promotion of cytotoxic T lymphocyte activation infiltration. Therefore, potential multimodal agent synergistic phototherapeutic, chemotherapeutic, immunotherapeutic effects.

Language: Английский

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Selective targeting of genes regulated by zinc finger proteins in endometriosis and endometrioid adenocarcinoma by zinc niflumato complex with neocuproine

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 24, 2025

Inadequate angiogenesis of endometriotic implants stimulated by the inflammatory microenvironment in uterine region leads to development gynecological diseases, which significantly reduce fertility and vitality young women. Angiogenic processes are controlled factors whose activities regulated at gene level reactive oxygen species (ROS), hypoxia-induced (HIFs), zinc-finger proteins (ZnFs) or posttranscriptionally via non-coding RNAs. The cooperation these is responsible for manifestation pathological stimuli form endometriosis body uterus, ovaries, peritoneum, from endometrioid carcinoma can develop. Molecules that control expression their intercalation target DNA sequence, such as [Zn(neo)(nif)2], could prevent hyperactivation pro-angiogenic pathways (decrease HIF-1α, VEGF-A, TGF-β1, COX2, ANG2/ANG1), formation ROS, risk neoplasticity. NSAID-metal complex [Zn(neo)(nif)2] shows an ability intercalate into ZNF3-7 sequence a higher rate, explain its effect on genes this transcription factor. In addition, affects ROS production Ca2+ level, possibly pointing mitochondrial dysfunction potential cause described apoptosis.

Language: Английский

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Pt(IV)-PROTAC Complexes with Synergistic Antitumor Activity and Enhanced Membrane Permeability

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims inducing DNA strand damage inhibiting repair. These showed good antiproliferative activity against a range cancer cell lines. Enhanced intracellular uptake platinum PROTAC observed. Multiple mechanisms action were identified, including the induction damage, disruption repair, activation mitochondrial-dependent apoptosis. One Pt(IV)-PROTACs, CW-2, excellent antitumor in xenograft mouse model. results suggest that represents promising strategy for development novel therapeutics.

Language: Английский

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Discovery of novel benzamide derivatives bearing benzamidophenyl and phenylacetamidophenyl scaffolds as potential antitumor agents via targeting PARP-1

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 251, P. 115243 - 115243

Published: March 2, 2023

Language: Английский

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Design, synthesis, and biological evaluation of a series of benzofuran[3,2-d]pyrimidine-4(3H)-one derivatives containing thiosemicarbazone analogs as novel PARP-1 inhibitors

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 139, P. 106759 - 106759

Published: Aug. 1, 2023

Language: Английский

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