RÉSUMÉ
Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.
RÉSUMÉ
The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC50 values. Compound lw13 effectively degraded Hsp90 at a concentration of only 0.05 µM. In addition, it can inhibit the metastasis of cancer cells and induce significant cell cycle arrest and apoptosis. Furthermore, lw13 demonstrated remarkable antitumor activity both in vitro and in vivo, and has a synergistic effect in combination with cisplatin. Moreover, lw13 can prevent the activation of the HER2/AKT/mTOR signaling pathway by indirectly reducing the levels of HER2 and AKT. This study paves the way for cancer treatment and provides valuable insights into the combination therapy of cervical cancer.
Sujet(s)
Antinéoplasiques , Apoptose , Prolifération cellulaire , Cisplatine , Tests de criblage d'agents antitumoraux , Protéines du choc thermique HSP90 , Tumeurs du col de l'utérus , Humains , Tumeurs du col de l'utérus/traitement médicamenteux , Tumeurs du col de l'utérus/anatomopathologie , Tumeurs du col de l'utérus/métabolisme , Cisplatine/pharmacologie , Femelle , Protéines du choc thermique HSP90/antagonistes et inhibiteurs , Protéines du choc thermique HSP90/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Apoptose/effets des médicaments et des substances chimiques , Synergie des médicaments , Relation structure-activité , Structure moléculaire , Relation dose-effet des médicaments , Animaux , Lignée cellulaire tumorale , Souris , Chimère ciblant la protéolyseRÉSUMÉ
Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.
Sujet(s)
Tumeurs du sein , Prolifération cellulaire , Résistance aux médicaments antinéoplasiques , Récepteur alpha des oestrogènes , Humains , Récepteur alpha des oestrogènes/métabolisme , Récepteur alpha des oestrogènes/antagonistes et inhibiteurs , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/métabolisme , Femelle , Animaux , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris , Aromatase/métabolisme , Inhibiteurs de l'aromatase/pharmacologie , Inhibiteurs de l'aromatase/composition chimique , Inhibiteurs de l'aromatase/synthèse chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Cellules MCF-7 , Protéolyse/effets des médicaments et des substances chimiques , Souris nude , Découverte de médicament , Relation structure-activitéRÉSUMÉ
Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.
Sujet(s)
Composés hétérocycliques bicycliques , Leucémie aigüe myéloïde , Mutation , Sulfonamides , Tests d'activité antitumorale sur modèle de xénogreffe , Tyrosine kinase-3 de type fms , Tyrosine kinase-3 de type fms/génétique , Tyrosine kinase-3 de type fms/antagonistes et inhibiteurs , Tyrosine kinase-3 de type fms/métabolisme , Humains , Animaux , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/anatomopathologie , Sulfonamides/pharmacologie , Composés hétérocycliques bicycliques/pharmacologie , Souris , Lignée cellulaire tumorale , Pyrazines/pharmacologie , Synergie des médicaments , Dérivés de l'aniline/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protéolyse/effets des médicaments et des substances chimiques , Femelle , Inhibiteurs de protéines kinases/pharmacologieRÉSUMÉ
The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2-(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 µM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.
Sujet(s)
Antiviraux , Interactions hydrophobes et hydrophiles , Thiourée , Antiviraux/pharmacologie , Antiviraux/composition chimique , Antiviraux/synthèse chimique , Humains , Chiens , Animaux , Thiourée/pharmacologie , Thiourée/analogues et dérivés , Thiourée/composition chimique , Relation structure-activité , Sous-type H1N1 du virus de la grippe A/effets des médicaments et des substances chimiques , Cellules rénales canines Madin-Darby , Protéolyse/effets des médicaments et des substances chimiques , Protéines virales/métabolisme , Protéines virales/composition chimique , Protéines virales/antagonistes et inhibiteurs , RNA replicase/antagonistes et inhibiteurs , RNA replicase/métabolisme , Résistance virale aux médicaments/effets des médicaments et des substances chimiquesRÉSUMÉ
Estrogen receptor (ER) ß and histone deacetylases (HDACs), when overexpressed, are associated closely with the occurrence and development of prostate cancer and are, therefore, considered important targets and biomarkers used in the clinical treatment of prostate cancer. The present study involved the design and synthesis of the first ERß and HDAC dual-target near-infrared fluorescent probe with both imaging capacity and antitumor activity for prostate cancer. Both P1 and P2 probes exhibited excellent ERß selectivity, with P1 being almost exclusively selective for ERß compared to ERα. In addition, P1 exhibited good optical properties, such as strong near-infrared emission, large Stokes shift, and better anti-interference ability, along with excellent imaging ability for living cells. P1 also exhibited potent inhibitory activity against HDAC6 and DU-145 cells, with IC50 values of 52 nM and 0.96 µM, respectively. Further, P1 was applied successfully for the in vivo imaging of prostate cancer in a mouse model, and significant in vivo antitumor efficacy was achieved. The developed dual-target NIR fluorescent probe is expected to serve as an effective tool in the research on prostate cancer, leading to novel insights for the theranostic study of diseases related to ERß and HDACs.
Sujet(s)
Histone deacetylases , Tumeurs de la prostate , Humains , Mâle , Souris , Animaux , Récepteur bêta des oestrogènes , Colorants fluorescents/pharmacologie , Médecine de précision , Tumeurs de la prostate/imagerie diagnostique , Tumeurs de la prostate/traitement médicamenteuxRÉSUMÉ
Proteolysis targeting chimera (PROTAC) technology, a groundbreaking strategy for degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. However, the real-time monitoring and visualization of protein degradation processes have been long-standing challenges in the realm of drug development. In this research, we sought to amalgamate the highly efficient protein-degrading capabilities of PROTAC technology with the visualization attributes of fluorescent probes, with the potential to pave the path for the design and development of a novel class of visual PROTACs. These novel PROTACs uniquely possess both fluorescence imaging and therapeutic characteristics, all with the goal of enabling real-time observations of protein degradation processes. Our approach involved the utilization of a high ER-targeting fluorescent probe, previously reported in our laboratory, which served as a warhead that specifically binds to the protein of interest (POI). Additionally, a VHL ligand for recruiting E3 ligase and linkers of various lengths were incorporated to synthesize a series of novel ER-inherent fluorescence PROTACs. Among them, compound A3 demonstrated remarkable efficiency in degrading ERα proteins (DC50 = 0.12 µM) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC50 = 0.051 µM). Furthermore, it exhibited impressive fluorescence imaging performance, boasting an emission wavelength of up to 582 nm, a Stokes shift of 116 nm, and consistent optical properties. These attributes make it especially suitable for the real-time, in situ tracking of ERα protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ERα+ breast cancer. This study not only broadens the application spectrum of PROTAC technology but also introduces a novel approach for real-time visualization of protein degradation processes, ultimately enhancing the diagnostic and treatment efficacy of PROTACs.
Sujet(s)
Récepteur alpha des oestrogènes , Chimère ciblant la protéolyse , Humains , Protéolyse , Récepteur alpha des oestrogènes/métabolisme , Médecine de précision , Ubiquitin-protein ligases/métabolisme , Protéines/métabolismeRÉSUMÉ
Endocrine resistance remains a significant problem in the clinical treatment of estrogen receptor α-positive (ERα+) breast cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity. Among them, compounds 35s and 35t exhibited the most promising antiproliferative and ERα degradation activity in multiple ERα+ BC cell lines bearing either wild-type or mutant ERα. Meanwhile, compounds 35s and 35t disrupted the microtubule network by restraining tubulin polymerization, evidenced by 35t inducing cell cycle arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds 35s and 35t remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα+ BC therapy, especially for the resistant variant.
Sujet(s)
Antinéoplasiques , Tumeurs du sein , Récepteurs des oestrogènes , Femelle , Humains , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/composition chimique , Tumeurs du sein/traitement médicamenteux , Lignée cellulaire tumorale , Prolifération cellulaire , Récepteur alpha des oestrogènes/métabolisme , Cellules MCF-7 , Récepteurs des oestrogènes/antagonistes et inhibiteurs , Tubuline/composition chimique , Modulateurs de la polymérisation de la tubuline/composition chimique , Modulateurs de la polymérisation de la tubuline/pharmacologieRÉSUMÉ
In view of the potential off-target effects of antitumor drugs, including proteolysis targeting chimera (PROTAC), certain toxic effects may be caused in normal tissues. Herein, based on the characteristics of the tumor microenvironment, we reported the first estrogen receptor α (ERα) targeting hypoxia-responsive PROTACs in order to improve their safety in breast cancer treatment by introducing two hypoxia-activated groups, nitroimidazole and nitrobenzene, into the ER ligand or E3 ligand of an active PROTAC, which has certain cytotoxicity in normal cells. Bioactivity studies showed that these hypoxia-responsive PROTACs exhibited excellent hypoxic responsiveness and ERα degradation activity under hypoxic conditions, and thus improved the toxic effects of the active PROTAC in normal cells. It is expected that our caged compounds provide a new strategy for precise functional control of PROTAC drugs for breast cancer treatment.
Sujet(s)
Tumeurs du sein , Humains , Femelle , Tumeurs du sein/anatomopathologie , Récepteur alpha des oestrogènes/métabolisme , Chimère ciblant la protéolyse , Ligands , Hypoxie/traitement médicamenteux , Hypoxie/métabolisme , Squelette/métabolisme , Squelette/anatomopathologie , Protéolyse , Microenvironnement tumoralRÉSUMÉ
Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.
Sujet(s)
Tumeurs du sein , Femelle , Humains , Aromatase/métabolisme , Inhibiteurs de l'aromatase/pharmacologie , Inhibiteurs de l'aromatase/usage thérapeutique , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Antagonistes des oestrogènes/pharmacologie , Récepteur alpha des oestrogènes/métabolisme , Récepteurs des oestrogènes/métabolismeRÉSUMÉ
Breast cancer (BC), a well-known estrogen-dependent cancer, is the most common cancer among women and the leading cause of cancer deaths. One of the most important therapeutic approaches for BC is endocrine therapy targeting estrogen receptor alpha (ERα) and thus blocking the estrogen receptor signaling pathway. Drugs, such as tamoxifen or fulvestrant, are developed based on this theory and have benefited numerous patients with BC for many years. However, many patients with advanced BC, such as tamoxifen-resistant BC, cannot benefit from these developed drugs anymore. Therefore, new drugs targeting ERα are urgently needed by patients with BC. Recently, elacestrant, a novel selective estrogen receptor degrader (SERD), was approved by the United States Food and Drug Administration (FDA), highlighting the importance of ERα degradation in endocrine therapy. Proteolysis targeting chimera (PROTAC) has been considered a powerful technique for targeting protein degradation (TPD). In this regard, we developed and studied a novel ERα degrader, which is a PROTAC-like SERD named 17e. We found that compound 17e can inhibit the growth of BC both in vitro and in vivo and induce the cell cycle arrest of BC. Importantly, 17e displayed no apparent toxicity toward healthy kidney and liver cells. Moreover, we observed that the presence of 17e led to a dramatic increase in the autophagy-lysosome pathway in an ERα-independent manner. Finally, we revealed that a decrease in MYC, a frequent deregulation oncogene in human cancers, was mediated by both ERα degradation and autophagy activation in the presence of 17e. Collectively, we discovered that compound 17e induced ERα degradation and exerts significant anti-cancer effects on BC mainly through promoting the autophagy-lysosome pathway and decreasing MYC level.
Sujet(s)
Tumeurs du sein , Humains , Femelle , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/métabolisme , Récepteur alpha des oestrogènes/métabolisme , Récepteurs des oestrogènes/métabolisme , Prolifération cellulaire , Antagonistes des oestrogènes/pharmacologie , Tamoxifène/pharmacologie , Points de contrôle du cycle cellulaire , Cellules MCF-7 , Lignée cellulaire tumoraleRÉSUMÉ
As an emerging therapeutic strategy, proteolysis-targeting chimeras (PROTACs) have been proven to be superior to traditional drugs in many aspects. However, due to their unique mechanism of action, existing methods for evaluating the degradation still have many limitations, which seriously restricts the development of PROTACs. In this methodological study, using direct stochastic optical reconstruction microscopy (dSTORM)-based single-cell protein quantitative analysis, we systematically investigated the dynamic degradation characteristics of FLT3 protein during PROTACs treatment. We found that the distribution of FLT3 varies between FLT3-ITD mutation and FLT3-WT cells. PROTACs had an obvious time-course effect on protein degradation and present two distinct phases; this provided a basis for deciding when to evaluate protein degradation. High concentrations of PROTACs were more effective than long-time administration because a higher Dmax was achieved. Two-color dSTORM-based colocalization analysis efficiently detected the proportion of ternary complexes, making it very useful in screening PROTACs. Taken together, our findings show that the dSTORM method is an ideal tool for evaluating PROTACs and will accelerate the development of new PROTACs.
Sujet(s)
Microscopie , Protéines , Protéines/métabolisme , ProtéolyseRÉSUMÉ
Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.
Sujet(s)
Antinéoplasiques/pharmacologie , Tumeurs du sein/traitement médicamenteux , Antagonistes des oestrogènes/pharmacologie , Récepteur alpha des oestrogènes/antagonistes et inhibiteurs , Inhibiteurs de désacétylase d'histone/pharmacologie , Histone deacetylases/métabolisme , Sulfonamides/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Tumeurs du sein/métabolisme , Tumeurs du sein/anatomopathologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Antagonistes des oestrogènes/synthèse chimique , Antagonistes des oestrogènes/composition chimique , Récepteur alpha des oestrogènes/métabolisme , Femelle , Inhibiteurs de désacétylase d'histone/synthèse chimique , Inhibiteurs de désacétylase d'histone/composition chimique , Humains , Cellules MCF-7 , Structure moléculaire , Relation structure-activité , Sulfonamides/synthèse chimique , Sulfonamides/composition chimiqueRÉSUMÉ
An electrochemically intramolecular functionalization of C(sp3)-H bonds with masked oxygen nucleophiles was developed. With KI as the catalyst and electrolyte, diverse trisubstituted 2-oxazolines were constructed in good to excellent yields. This newly developed electrochemical dehydrogenative approach features external oxidant-free and additive-free conditions.
RÉSUMÉ
A highly diastereo- and enantioselective aziridination of N-sulphonyl ketimines with unfunctionalized ketones was reported. In this efficient method, a sequential direct asymmetric Mannich reaction and oxidative C-H amination were involved, which enabled a straightforward route to multisubstituted-fused aziridines in one pot. More importantly, two different products could be selectively obtained in the reaction by adding or removing a metal additive.
RÉSUMÉ
A copper/iodine cocatalyzed decarboxylative cyclization of α-amino acids is described. Starting from the readily available amino acids and either 2-benzoylpyridines or 2-benzoylquinolines, 1,3-disubstituted imidazo[1,5-a]pyridines and 1,3-disubstituted imidazo[1,5-a]quinolines were prepared in excellent yields.