RESUMEN
Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.
Asunto(s)
Antineoplásicos , Iridio , Metano , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Iridio/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metano/análogos & derivados , Metano/química , Metano/farmacología , Proteínas de Microfilamentos/metabolismo , Metástasis de la Neoplasia , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , MasculinoRESUMEN
Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.
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Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Inmunoconjugados/química , Compuestos de Amonio Cuaternario/química , Oligopéptidos/química , Línea Celular TumoralRESUMEN
Globally, breast cancer is a primary contributor to cancer-related fatalities and illnesses among women. Consequently, there is a pressing need for safe and effective treatments for breast cancer. Bioactive compounds from endophytic fungi that live in symbiosis with medicinal plants have garnered significant interest in pharmaceutical research due to their extensive chemical composition and prospective medicinal attributes. This review underscores the potentiality of fungal endophytes as a promising resource for the development of innovative anticancer agents specifically tailored for breast cancer therapy. The diversity of endophytic fungi residing in medicinal plants, success stories of key endophytic bioactive metabolites tested against breast cancer and the current progress with regards to in vivo studies and clinical trials on endophytic fungal metabolites in breast cancer research forms the underlying theme of this article. A thorough compilation of putative anticancer compounds sourced from endophytic fungi that have demonstrated therapeutic potential against breast cancer, spanning the period from 1990 to 2022, has been presented. This review article also outlines the latest trends in endophyte-based drug discovery, including the use of artificial intelligence, machine learning, multi-omics approaches, and high-throughput strategies. The challenges and future prospects associated with fungal endophytes as substitutive sources for developing anticancer drugs targeting breast cancer are also being highlighted.
RESUMEN
A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Quinasas Janus , Purinas/farmacología , Línea Celular Tumoral , Proliferación CelularRESUMEN
Over the years, natural compounds have become a significant advancement in cancer treatment, primarily due to their effectiveness, safety, bio-functionality, and wide range of molecular structures. They are now increasingly preferred in drug discovery due to these attributes. These compounds, whether occurring naturally or with synthetic modifications, find applications in various fields like biology, medicine, and engineering. While chemotherapy has been a successful method for treating cancer, it comes with systemic toxicity. To address this issue, researchers and medical practitioners are exploring the concept of combinational chemotherapy. This approach aims to reduce toxicity by using a mix of natural substances and their derivatives in clinical trials and prescription medications. Among the most extensively studied natural anticancer compounds are quercetin, curcumin, vincristine, and vinblastine. These compounds play crucial roles as immunotherapeutics and chemosensitizers, both as standalone treatments and in combination therapies with specific mechanisms. This review article provides a concise overview of the functions, potentials, and combinations of natural anticancer compounds in cancer treatment, along with their mechanisms of action and clinical applications.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Fitoquímicos/uso terapéutico , Fitoquímicos/farmacología , Fitoquímicos/química , Animales , Extractos Vegetales/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/químicaRESUMEN
Cancer stands as a prominent global cause of mortality, with chemotherapy using synthetic drugs being the predominant treatment method. Despite its high success rate, this approach is constrained by substantial side effects. Herbal medicines, known for their diverse bioactive components, exhibit promising anticancer attributes. The drug delivery systems can improve the precision of delivering these herbal compounds, enhancing efficacy while minimizing potential side effects. Various platforms, such as nanoparticle-based carriers, liposomes, and polymeric micelles, are investigated for encapsulating and delivering herbal components to cancer cells. These systems not only enhance the bioavailability of herbal compounds but also facilitate controlled release, sustained drug circulation, and improved cellular uptake. This comprehensive review focuses on the recent advancement in the field of drug delivery systems employed in the delivery of plant-derived anticancer compounds. It categorizes carriers into organic and inorganic nanoparticles, addressing their application in enhancing the safety and efficacy of plant-derived anticancer compounds alongside associated challenges. The review concludes by outlining recent investigations into drug delivery systems aimed at increasing the efficacy of plant-derived anticancer compounds. Future research in this field should emphasize experiments in animal models and potential clinical translation.