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1.
Biochem Pharmacol ; 224: 116246, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38685282

RESUMO

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays an essential role in regulating cell proliferation, migration and invasion through both kinase-dependent enzymatic function and kinase-independent scaffolding function. The overexpression and activation of FAK is commonly observed in various cancers and some drug-resistant settings. Therefore, targeted disruption of FAK has been identified as an attractive strategy for cancer treatment. To date, numerous structurally diverse inhibitors targeting distinct domains of FAK have been developed, encompassing kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors, with several FAK inhibitors advanced to clinical trials. Moreover, given the critical role of FAK scaffolding function in signal transduction, FAK-targeted PROTACs have also been developed. Although no current FAK-targeted therapeutics have been approved for the market, the combination of FAK inhibitors with other anticancer drugs has shown considerable promise in the clinic. This review provides an overview of current drug discovery strategies targeting FAK, including the development of FAK inhibitors, FAK-based dual-target inhibitors and proteolysis-targeting chimeras (PROTACs) in both literature and patent applications. Accordingly, their design and optimization process, mechanisms of action and biological activities are discussed to offer insights into future directions of FAK-targeting drug discovery in cancer therapy.


Assuntos
Antineoplásicos , Proteína-Tirosina Quinases de Adesão Focal , Neoplasias , Inibidores de Proteínas Quinases , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Animais , Proteólise/efeitos dos fármacos , Terapia de Alvo Molecular/métodos
2.
Eur J Med Chem ; 270: 116393, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38588626

RESUMO

Estrogen receptor alpha (ERα), a nuclear transcription factor, is a well-validated therapeutic target for more than 70% of all breast cancers (BCs). Antagonizing ERα either by selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) forms the foundation of endocrine therapy and has achieved great success in the treatment of ERα positive (ERα+) BCs. Unfortunately, despite initial effectiveness, endocrine resistance eventually emerges in up to 30% of ERα+ BC patients and remains a significant medical challenge. Several mechanisms implicated in endocrine resistance have been extensively studied, including aberrantly activated growth factor receptors and downstream signaling pathways. Hence, the crosstalk between ERα and another oncogenic signaling has led to surge of interest to develop combination therapies and dual-target single agents. This review briefly introduces the synergisms between ERα and another anticancer target and summarizes the recent advances of ERα-based dual-targeting inhibitors from a medicinal chemistry perspective. Accordingly, their rational design strategies, structure-activity relationships (SARs) and biological activities are also dissected to provide some perspectives on future directions for ERα-based dual target drug discovery in BC therapy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptores de Estrogênio/metabolismo , Antagonistas de Estrogênios/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Resistencia a Medicamentos Antineoplásicos
3.
J Med Chem ; 67(7): 5567-5590, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38512060

RESUMO

Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment for patients expressing the constitutively active AR splice variants, such as AR-V7. Herein, we report the structure-activity relationship studies of 55 N-heterocycle-substituted hydantoins, which identified the structural motifs required for AR/AR-V7 degradation. Among them, the most potent compound 27c exhibited selective AR/AR-V7 degradation over other hormone receptors and excellent antiproliferative activities in LNCaP and 22RV1 cells. RNA sequence analysis confirmed that 27c effectively suppressed transcriptional activity of the AR signaling pathway. Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Linhagem Celular Tumoral , Transdução de Sinais , Relação Estrutura-Atividade , Nitrilas/farmacologia , Resistencia a Medicamentos Antineoplásicos
4.
J Med Chem ; 67(5): 3606-3625, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38375763

RESUMO

DNA polymerase theta (Polθ) has recently emerged as a new attractive synthetic lethal target involved in DNA damage repair. Inactivating Polθ alone or in combination with PARP inhibitors has demonstrated substantial therapeutic potential against tumors with homologous recombination (HR) defects such as alternation of BRCA genes. Herein, we report the design and proof of concept of a highly potent dual Polθ/PARP inhibitor 25d, which exhibited low nanomolar inhibitory activities against both Polθ and PARP1. Compared to combination treatment, 25d demonstrated superior antitumor efficacy in both MDA-MB-436 cells and xenografts by inducing more DNA damage and apoptosis. Importantly, 25d retained sensitivity in PARP inhibitor-resistant MDA-MB-436 cells with 53BP1 defect. Altogether, these findings illustrate the potential advantages of 25d, a first-in-class dual Polθ/PARP inhibitor, over monotherapy in treating HR-deficient tumors, including those with acquired PARP inhibitor resistance.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias/tratamento farmacológico , Reparo do DNA , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Recombinação Homóloga , Linhagem Celular Tumoral
5.
Bioorg Chem ; 141: 106919, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37871388

RESUMO

Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.


Assuntos
Neoplasias da Mama , Antagonistas do Receptor de Estrogênio , Humanos , Camundongos , Animais , Feminino , Receptor alfa de Estrogênio , Receptores de Estrogênio , Cristalografia por Raios X , Neoplasias da Mama/tratamento farmacológico , Células MCF-7 , Antagonistas de Estrogênios
6.
ACS Nano ; 17(15): 15165-15179, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37490051

RESUMO

Oxidative stress accompanying the reactive oxygen species (ROS) burst governs immunocyte infiltration, activation, and differentiation in tumor microenvironments and thus can elicit robust antitumor immunity. Here, we identify a photoactive metal-organic coordination polymer (MOCP), composed of an organometallic core formed by cytotoxic mitoxantrone (MTX) acylates and photosensitive Ru(BIQ)-HDBB [BIQ = 2,2'-biquinoline, HDBB = 4,4'-di(4-benzoato)-2,2'-bipyridine] linked by Fe(II) ions via coordinate covalent bonds and an amphipathic shell encapsulating cholesterol-modified siRNA against GPX4 (siGPX4) via hydrophobic force, to precisely amplify intracellular oxidative storm. MOCPs simultaneously encapsulated MTX, Ru, and siGPX4 with efficiencies >98% and loaded Fe with efficiencies of ∼0.49%. With longer blood circulation and higher tumor accumulation, MOCPs with a 670 nm LED irradiation generate abundant ROS to induce biomembrane dysfunction and subsequently contribute to ferroptotic and immunogenic cell death, which drive tumor-associated antigen-specific immunity. MTX analogs contributed to Type I immunogenic cell death (ICD), while oxidative storm served as a damager for endo/lysosomal escape, an initiator for ferroptosis, and an inducer for type II ICD. Moreover, the blockade of CD73 that reduces extoATP catabolism unleashes immunosuppression, finally enhancing antitumor immune stimulation of MOCPs to promote orthotopic mammary cancer regression and prevent postoperative advanced cancer from recurrence and metastasis. MOCPs by exposing sufficient antigenicity thus provide a platform to synergize immune checkpoint inhibitors for the treatment of immunologically cold tumors.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Estresse Oxidativo , Metais , Linhagem Celular Tumoral , Microambiente Tumoral
7.
Bioorg Chem ; 134: 106459, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36924653

RESUMO

Both estrogen receptor α (ERα) and histone deacetylases (HDACs) are valid therapeutic targets for anticancer drug development. Combination therapies using diverse ERα antagonists or degraders and HDAC inhibitors have been proven effective in endocrine-resistant ER + breast cancers based on the crosstalk between ERα and HDAC pathway. In this study, we reported the optimization of a series of methoxyphenyl- or pyridinyl- substituted tetrahydroisoquinoline-hydroxamates, which were optimized from 31, a dual ERα degrader/HDAC inhibitor previously reported by our group. Most of the synthesized compounds displayed potent ERα degradation efficacy and antiproliferative activity. Among them, A04 demonstrated the best anti-proliferation activity (MCF-7 IC50 = 1.96 µM) and HDAC6 inhibitory activity (HDAC6 IC50 = 25.96 nM), which is slightly more potent than the lead compound 31 (MCF-7 IC50 = 4.38 µM, HDAC6 IC50 = 63.03 nM). In addition, compound A04 exerted ERα-independent HDAC6-inhibiting effect without agonistic activity in endometrial cells. These results demonstrated that A04 is a novel and promising dual ERα degrader/HDAC inhibitor worthy of further development.


Assuntos
Antineoplásicos , Neoplasias da Mama , Tetra-Hidroisoquinolinas , Humanos , Feminino , Inibidores de Histona Desacetilases/química , Receptor alfa de Estrogênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Proliferação de Células , Antineoplásicos/química , Relação Estrutura-Atividade , Linhagem Celular Tumoral
8.
Bioorg Chem ; 130: 106263, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36375350

RESUMO

Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of B-cell related malignancies. Irreversible inhibition of BTK by a covalent inhibitor has been proved to be a clinically effective therapy. However, most irreversible BTK inhibitors also inhibit other kinases including JAK3 and EGFR, leading to some adverse events. Herein, we reported the structure-based design and optimization of a series of irreversible BTK inhibitors bearing the 6-amino-1,3,5-triazine scaffold. Most of the synthesized compounds demonstrated considerable BTK inhibition and improved anti-proliferative activity against Raji and Ramos cells. Among them, compound C11 exhibited potent BTK inhibition (BTK IC50 = 17.0 nM) and a desirable selectivity profile especially over EGFR. Moreover, C11 effectively blocked activation of BTK and downstream signaling, arrested the cell cycle in G0/G1 phase and induced apoptosis in Raji cells. Its irreversible binding mode was further investigated by both molecular modeling and a washout experiment. Collectively, C11 is a novel selective irreversible BTK inhibitor worthy of further in-depth research.


Assuntos
Inibidores de Proteínas Quinases , Triazinas , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Tirosina Quinase da Agamaglobulinemia , Relação Estrutura-Atividade , Triazinas/farmacologia , Receptores ErbB/metabolismo
9.
J Med Chem ; 65(24): 16128-16154, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36459083

RESUMO

Prostate cancer (PC), the second most prevalent malignancy in men worldwide, has been proven to depend on the aberrant activation of androgen receptor (AR) signaling. Long-term androgen deprivation for the treatment of PC inevitably leads to castration-resistant prostate cancer (CRPC) in which AR remains a crucial oncogenic driver. Thus, there is an urgent need to develop new strategies to address this unmet medical need. Targeting AR for degradation has recently been in a vigorous development stage, and accumulating clinical studies have highlighted the benefits of AR degraders in CRPC patients. Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure-activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios , Androgênios , Transdução de Sinais
10.
J Steroid Biochem Mol Biol ; 223: 106154, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35870675

RESUMO

Endocrine therapy is widely used in clinic for breast cancer treatment, but long-term treatment inevitably causes drug resistance. Most of endocrine therapy-resistant breast cancers continue to depend on ERα signaling for growth and survival. In this regard, small molecule-induced ERα degradation, i.e. proteolysis targeting chimeras (PROTACs), represents an effective strategy to overcome endocrine resistance. Herein, we describe the design, synthesis, and biological evaluation of novel ERα-targeting PROTACs, wherein a E3 ligase ligand was attached to the 11ß-position of estradiol via various linkers. Our efforts have identified a potent ERα PROTAC 15b that achieved excellent ERα degradation activity (DC50 = 67 nM) and induced comparable inhibition of cell growth to that of fulvestrant in MCF-7 cells. Besides, 15b displayed antagonistic effects in uterine cells and favorable physicochemical properties, making it as a good lead compound for further development as anti-breast agents.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Estradiol/farmacologia , Estradiol/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Fulvestranto/farmacologia , Ligantes , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/uso terapêutico
11.
J Med Chem ; 64(23): 17098-17114, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34812040

RESUMO

The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.


Assuntos
Proteína Forkhead Box M1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Ligantes , Proteólise
12.
Eur J Med Chem ; 226: 113870, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34610548

RESUMO

Concomitant inhibition of estrogen receptor alpha (ERα) and histone deacetylase (HDAC) signaling has been proven effective in endocrine-resistant ER+ breast cancers. Herein, a series of tetrahydroisoquinoline (THIQ)-hydroxamate conjugates were rationally designed and synthesized as dual SERDs/HDAC inhibitors by incorporating the hydroxamate, a known HDAC pharmacophore, into a privileged THIQ scaffold of selective ERα degraders (SERDs). Some of these THIQ-hydroxamate conjugates displayed remarkable HDAC6 inhibition and improved antiproliferative activity against MCF-7 cells. Particularly, the most potent HDAC inhibitor 19k also exhibits potent ERα binding affinity, good ERα degradation efficacy and the best antiproliferative activity. Besides, 19k displayed superior antitumor efficacy than the drug combination (Fulvestrant + SAHA) through promoting ERα degradation and histone acetylation in an MCF-7 xenograft model, without causing observable toxicity. Collectively, this study validates the therapeutic potential of a dual-acting compound with potent ERα degradation efficacy and HDAC6 inhibition in breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenvolvimento de Medicamentos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Células Tumorais Cultivadas
13.
Bioorg Med Chem ; 47: 116395, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34509864

RESUMO

Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. In the present study, series of novel 6-OH-benzothiophene (BT) derivatives targeting ERα and deriving from Raloxifene were designed, synthesized, and biologically evaluated as covalent antagonists. Driven by the antiproliferative efficacy in ER+ breast cancer cells, our chemical optimization finally led to compound 19d that with potent antagonistic activity in ER+ tumor cells while without agonistic activity in endometrial cells. Moreover, the docking simulation was carried out to elucidate the binding mode, revealing 19d as an antagonist and covalently binding to the cysteine residue at the 530 position of ER helix H11.


Assuntos
Desenho de Fármacos , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Tiofenos/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
14.
Acta Pharm Sin B ; 11(5): 1300-1314, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34094835

RESUMO

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.

15.
Eur J Med Chem ; 221: 113543, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34022716

RESUMO

Endocrine therapy (ET) has benefited patients with estrogen receptor alpha (ERα) positive breast cancer for decades. Selective estrogen receptor modulator (SERM) such as Tamoxifen represents the clinical standard of care (SoC). Despite the therapeutic importance of current SoC agents, 30-50% of prolonged treatment patients inevitably generated resistant tumor cells, usually eventually suffered tumor relapse and developed into metastatic breast cancer (MBC), which was the leading cause of female cancer-related mortality. Among these, most resistant tumors remained dependent on ERα signaling, which reignited the need for the next generation of ERα related agents. We hypothesized that selective estrogen receptor covalent antagonists targeting ERα would provide a therapeutic alternative. In the current work, series of novel benzothiophene hybrids bearing electrophile moieties were synthesized and biologically evaluated. The representative analogue 15c exhibited potent anti-proliferative effect in MCF-7 cell lines in vitro, and further mechanism studies confirmed the necessity of covalent bonding. More importantly, 15c could attenuate the expression of TFF-1, GREB-1 and downregulate the levels of cellular ERα protein.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Antagonistas do Receptor de Estrogênio/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Tiofenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Receptor de Estrogênio/síntese química , Antagonistas do Receptor de Estrogênio/química , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Células Tumorais Cultivadas
16.
Bioorg Med Chem ; 37: 116107, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33735799

RESUMO

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer with high mortality and recurrence rates. Hecogenin, a steroidal sapogenin, is reported as a potential anti-tumor agent against breast cancer. However, the moderate activity limits its further application in clinical. With the aim to identify novel analogues that are especially efficacious in therapy of TNBC, a series of novel hecogenin thiosemicarbazone and semicarbazone derivatives were designed, synthesized and biologically evaluated. Screening of cytotoxicity revealed that 4c could potently inhibit the proliferation of breast cancer cells (MCF-7 and MDA-MB-231 cells), lung cancer cells (A549) and colon cancer cells (HT-29) at low µM level. Importantly, further mechanism studies indicated the ability of 4c in inducing apoptosis of MDA-MB-231 cells by arresting the cell cycle. Moreover, 4c notably suppressed the migration and invasion of MDA-MB-231 cells compared to its parent hecogenin at the equal concentration.


Assuntos
Antineoplásicos/farmacologia , Sapogeninas/farmacologia , Tiossemicarbazonas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Sapogeninas/síntese química , Sapogeninas/toxicidade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/toxicidade
17.
Bioorg Chem ; 109: 104714, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33618254

RESUMO

Selective estrogen receptor degraders (SERDs) not only block ERα activity but degrade this receptor at the same time and are effective in relapsed ERα positive breast cancer patients who have accepted other endocrine therapies. Herein, through scaffold hopping of coumarin skeleton, a series of 2H-chromene-3-carbonyl-based SERDs with phenyl acrylic acid group as the side chain were designed and synthesized. Compound XH04 containing 7-hydroxy-2H-chromene-3-carbonyl skeleton exhibited the most potent activities in 2D (IC50 = 0.8 µM) and 3D cells culture models (MCF-7) and had the best ERα binding affinity as well. Furthermore, the significant antiestrogen property of compound XH04 was confirmed by inhibiting the expression of progesterone receptor (PgR) mRNA in MCF-7 cells. On the other hand, the outgoing ERα degradation property of compound XH04 was qualitatively and quantificationally verified by immunofluorescence analysis and Western blot assay in MCF-7 cells. Besides, compound XH04 repressed the expression level of Ki67 in MCF-7 cells and induced the apoptosis increase of this tumor cells in a dose-dependent manner like approved-SERD fulvestrant (2), while compound XH04 exhibited better preliminary pharmacokinetics in human and rat liver microsomes in vitro and a lower LogD7.4 value than fulvestrant. And further molecular docking study revealed that compound XH04 possessed a proverbial and typical binding model with ERα like other reported SERD. All these results confirmed that 7-hydroxy-2H-chromene-3-carbonyl structure could be a feasible skeleton for design of ERα antagonists including SERDs and compound XH04 is a promising candidate for further development of ERα + breast cancer therapy agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Neoplasias da Mama , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo
18.
Eur J Med Chem ; 209: 112910, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049605

RESUMO

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive in vitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising in vivo FXR agonistic activity.


Assuntos
Isoxazóis/síntese química , Doenças Metabólicas/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Administração Oral , Animais , Benzotiazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 28(23): 115763, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32992255

RESUMO

A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 µM and 0.52 µM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.


Assuntos
Antineoplásicos/química , Chalconas/química , Esteroides/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
20.
Eur J Med Chem ; 208: 112865, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987316

RESUMO

Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
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