RESUMO
BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Receptor trkA , Receptor trkB , Receptor trkC , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/genética , Receptor trkA/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/genética , Receptor trkC/antagonistas & inibidores , Linhagem Celular Tumoral , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Ratos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pirazóis/farmacologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Pirimidinas/farmacologia , Mutação , Feminino , Glicoproteínas de MembranaRESUMO
Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed ('hot') tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1RESUMO
High rates of recurrence and treatment resistance in the most common malignant adult brain cancer, glioblastoma (GBM), suggest that monotherapies are not sufficiently effective. Combination therapies are increasingly pursued, but the possibility of adverse drug-drug interactions may preclude clinical implementation. Developing single molecules with multiple targets is a feasible alternative strategy to identify effective and tolerable pharmacotherapies for GBM. Here, we report the development of a novel, first-in-class, dual aurora and lim kinase inhibitor termed F114. Aurora kinases and lim kinases are involved in neoplastic cell division and cell motility, respectively. Due to the importance of these cellular functions, inhibitors of aurora kinases and lim kinases are being pursued separately as anti-cancer therapies. Using in vitro and ex vivo models of GBM, we found that F114 inhibits GBM proliferation and invasion. These results establish F114 as a promising new scaffold for dual aurora/lim kinase inhibitors that may be used in future drug development efforts for GBM, and potentially other cancers.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Quinases Lim/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase A/metabolismo , Aurora Quinase B/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Quinases Lim/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) remains a crucial factor endangering human health. Gene-based clinical predictions could be of great help for cancer intervention strategies. Here, we tried to build a gene-based survival score (SS) for LUAD via analyzing multiple transcriptional datasets. METHODS: We first acquired differentially expressed genes between tumors and normal tissues from intersections of four LUAD datasets. Next, survival-related genes were preliminarily unscrambled by univariate Cox regression and further filtrated by LASSO regression. Then, we applied PCA to establish a comprehensive SS based on survival-related genes. Subsequently, we applied four independent LUAD datasets to evaluate prognostic prediction of SS. Moreover, we explored associations between SS and clinicopathological features. Furthermore, we assessed independent predictive value of SS by multivariate Cox analysis and then built prognostic models based on clinical stage and SS. Finally, we performed pathway enrichments analysis and investigated immune checkpoints expression underlying SS in four datasets. RESULTS: We established a 13 gene-based SS, which could precisely predict OS and PFS of LUAD. Close relations were elicited between SS and canonical malignant indictors. Furthermore, SS could serve as an independent risk factor for OS and PFS. Besides, the predictive efficacies of prognostic models were also reasonable (C-indexes: OS, 0.7; PFS, 0.7). Finally, we demonstrated enhanced cell proliferation and immune escape might account for high clinical risk of SS. CONCLUSIONS: We built a 13 gene-based SS for prognostic prediction of LUAD, which exhibited wide applicability and could contribute to LUAD management.
Assuntos
Adenocarcinoma de Pulmão/mortalidade , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Neoplasias Pulmonares/mortalidade , Transcriptoma , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3â¯nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.
Assuntos
Ácidos Carboxílicos/farmacologia , Cromanos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
A dynamic actin cytoskeleton is necessary for viral entry, intracellular migration, and virion release. For HIV-1 infection, during entry, the virus triggers early actin activity by hijacking chemokine coreceptor signaling, which activates a host dependency factor, cofilin, and its kinase, the LIM domain kinase (LIMK). Although knockdown of human LIM domain kinase 1 (LIMK1) with short hairpin RNA (shRNA) inhibits HIV infection, no specific small-molecule inhibitor of LIMK has been available. Here, we describe the design and discovery of novel classes of small-molecule inhibitors of LIMK for inhibiting HIV infection. We identified R10015 as a lead compound that blocks LIMK activity by binding to the ATP-binding pocket. R10015 specifically blocks viral DNA synthesis, nuclear migration, and virion release. In addition, R10015 inhibits multiple viruses, including Zaire ebolavirus (EBOV), Rift Valley fever virus (RVFV), Venezuelan equine encephalitis virus (VEEV), and herpes simplex virus 1 (HSV-1), suggesting that LIMK inhibitors could be developed as a new class of broad-spectrum antiviral drugs.IMPORTANCE The actin cytoskeleton is a structure that gives the cell shape and the ability to migrate. Viruses frequently rely on actin dynamics for entry and intracellular migration. In cells, actin dynamics are regulated by kinases, such as the LIM domain kinase (LIMK), which regulates actin activity through phosphorylation of cofilin, an actin-depolymerizing factor. Recent studies have found that LIMK/cofilin are targeted by viruses such as HIV-1 for propelling viral intracellular migration. Although inhibiting LIMK1 expression blocks HIV-1 infection, no highly specific LIMK inhibitor is available. This study describes the design, medicinal synthesis, and discovery of small-molecule LIMK inhibitors for blocking HIV-1 and several other viruses and emphasizes the feasibility of developing LIMK inhibitors as broad-spectrum antiviral drugs.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , HIV-1/efeitos dos fármacos , Quinases Lim/antagonistas & inibidores , Liberação de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Antivirais/isolamento & purificação , Células Cultivadas , Ebolavirus/efeitos dos fármacos , Vírus da Encefalite Equina Venezuelana/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/isolamento & purificação , HIV-1/fisiologia , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Vírus da Febre do Vale do Rift/efeitos dos fármacosRESUMO
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets with clinically available drugs are lacking. Here, we report that protein levels of the Rho-associated protein kinases (ROCK1 and ROCK2), p70 S6 kinase (S6K), and mammalian target of rapamycin (mTOR) were increased in PSP and CBD brains. RNAi depletion of ROCK1 or ROCK2 reduced tau mRNA and protein level in human neuroblastoma cells. However, additional phenotypes were observed under ROCK2 knockdown, including decreased S6K and phosphorylated mTOR levels. Pharmacologic inhibition of Rho kinases in neurons diminished detergent-soluble and -insoluble tau through a combination of autophagy enhancement and tau mRNA reduction. Fasudil, a clinically approved ROCK inhibitor, suppressed rough eye phenotype and mitigated pathogenic tau levels by inducing autophagic pathways in a Drosophila model of tauopathy. Collectively, these findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in PSP and CBD. SIGNIFICANCE STATEMENT: Studies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) suggest that mitigating pathogenic tau levels is a rational strategy for tauopathy treatment. In this report, the Rho-associated protein kinases (ROCK1 and ROCK2) are identified as novel drug targets for PSP and CBD. We show that elevated insoluble tau levels are associated with increased ROCK1 and ROCK2 in PSP and CBD brains, whereas experiments in cellular and animal models identify pharmacologic inhibition of ROCKs as a mechanism-based approach to reduce tau levels. Our study correlates bona fide changes in PSP and CBD brains with cellular models, identifies drug targets, and tests the therapeutic in vivo.
Assuntos
Doenças dos Gânglios da Base/patologia , Encéfalo/metabolismo , Paralisia Supranuclear Progressiva/patologia , Quinases Associadas a rho/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Drosophila , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Degeneração Neural/patologia , Neuroblastoma/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Lim kinase (Limk), a proline/serine-rich sequence, can regulate the polymerization of the actin filaments by phosphorylating, and it is found to be highly involved in various human diseases. In this paper, 47 reported Limk1 inhibitors with bis-aryl urea scaffold were used to design potent and selective Limk inhibitors by computational approaches. Firstly, the structure-Limk1 activity relationship models (3D-QSAR) and structure-Limk1/ROCK2 selectivity relationship models (3D-QSSR) were developed and both 3D-QSAR and 3D-QSSR models showed good correlative and predictive abilities. Then, the molecular docking and molecular dynamics (MD) simulations were employed to validate the optimal docking conformation and explore the binding affinities. Finally, five new compounds were designed and all of them exhibited good Limk1 inhibition and Limk1/ROCK2 selectivity after synthesis and biological evaluation, which demonstrated that the obtained information from computational studies were valuable to guide Limk inhibitors' design.
Assuntos
Quinases Lim/antagonistas & inibidores , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Humanos , Quinases Lim/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos de Fenilureia/síntese química , Inibidores de Proteínas Quinases/síntese química , Relação Quantitativa Estrutura-Atividade , Quinases Associadas a rho/químicaRESUMO
An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Recombinantes/química , Bibliotecas de Moléculas Pequenas/química , Ureia/química , Quinases Associadas a rho/antagonistas & inibidores , Sítios de Ligação , Proteínas Quinases Dependentes de AMP Cíclico/química , Descoberta de Drogas , Ensaios Enzimáticos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas/síntese química , Eletricidade Estática , Ureia/análogos & derivados , Ureia/síntese química , Quinases Associadas a rho/químicaRESUMO
Alzheimer's disease (AD) is the leading cause of dementia and has no cure. Genetic, cell biological, and biochemical studies suggest that reducing amyloid-ß (Aß) production may serve as a rational therapeutic avenue to delay or prevent AD progression. Inhibition of RhoA, a Rho GTPase family member, is proposed to curb Aß production. However, a barrier to this hypothesis has been the limited understanding of how the principal downstream effectors of RhoA, Rho-associated, coiled-coil containing protein kinase (ROCK) 1 and ROCK2, modulate Aß generation. Here, we report that ROCK1 knockdown increased endogenous human Aß production, whereas ROCK2 knockdown decreased Aß levels. Inhibition of ROCK2 kinase activity, using an isoform-selective small molecule (SR3677), suppressed ß-site APP cleaving enzyme 1 (BACE1) enzymatic action and diminished production of Aß in AD mouse brain. Immunofluorescence and confocal microscopy analyses revealed that SR3677 alters BACE1 endocytic distribution and promotes amyloid precursor protein (APP) traffic to lysosomes. Moreover, SR3677 blocked ROCK2 phosphorylation of APP at threonine 654 (T654); in neurons, T654 was critical for APP processing to Aß. These observations suggest that ROCK2 inhibition reduces Aß levels through independent mechanisms. Finally, ROCK2 protein levels were increased in asymptomatic AD, mild cognitive impairment, and AD brains, demonstrating that ROCK2 levels change in the earliest stages of AD and remain elevated throughout disease progression. Collectively, these findings highlight ROCK2 as a mechanism-based therapeutic target to combat Aß production in AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Quinases Associadas a rho/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , DNA/genética , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imuno-Histoquímica , Lentivirus/genética , Camundongos , Microscopia Confocal , Plasmídeos/genética , Técnicas Estereotáxicas , Espectrometria de Massas em TandemRESUMO
Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3'-cyano-4'-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anticancer function of these inhibitors may be partially due to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low cytochrome P450 inhibition and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Enzima Desubiquitinante CYLD , Feminino , Humanos , Macrófagos , Masculino , Camundongos , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/química , Interferência de RNA , RNA Interferente Pequeno , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Selectivity is a primary focus in medicinal chemistry for ATP-competitive kinase inhibitors due to the highly conserved ATP binding pockets in the kinome. A decade of medicinal chemistry efforts has been carried out to develop selective inhibitors for JNKs, resulting in the identification of numerous promising scaffolds that even exhibit isoform selectivity. Thiophene-indazole is one of the scaffolds explored for isoform selectivity. Some iterations of this scaffold have also shown selectivity for p38α. In this study, we utilized four compounds derived from thiophene-indazole to investigate the mechanisms of selectivity for JNK3 and p38α. We determined crystal structures of the inhibitors bound to either JNK3 or p38α and subjected them to molecular dynamics (MD) simulations to understand the binding mechanism and critical interactions that govern affinity and selectivity for these two important kinases. The findings from this study provides valuable information for improving current lead inhibitors and developing a new generation of JNK3 isoform inhibitors.
RESUMO
STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound 9 had an STK17A inhibitory IC50 of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.
RESUMO
SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability.
Assuntos
Aminoácidos/química , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Quinazolinas/química , Quinases Associadas a rho/antagonistas & inibidores , Sítios de Ligação , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinazolinas/síntese química , Quinazolinas/metabolismo , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.
Assuntos
Antineoplásicos/química , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sítios de Ligação , Caseína Quinase 1 épsilon/metabolismo , Caseína Quinase Idelta/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular , Meia-Vida , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Purinas/química , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Therapeutic developments targeting acute myeloid leukemia (AML) have been in the pipeline for five decades and have recently resulted in the approval of multiple targeted therapies. However, there remains an unmet need for molecular treatments that can deliver long-term remissions and cure for this heterogeneous disease. Previously, a wide range of small molecule drugs were developed to target sub-types of AML, mainly in the relapsed and refractory setting; however, drug resistance has derailed the long-term efficacy of these as monotherapies. Recently, the small molecule venetoclax was introduced in combination with azacitidine, which has improved the response rates and the overall survival in older adults with AML compared to those of chemotherapy. However, this regimen is still limited by cytotoxicity and is not curative. Therefore, there is high demand for therapies that target specific abnormalities in AML while sparing normal cells and eliminating leukemia-initiating cells. Despite this, the urgent need to develop these therapies has been hampered by the complexities of this heterogeneous disease, spurring the development of innovative therapies that target different mechanisms of leukemogenesis. This review comprehensively addresses the development of novel targeted therapies and the translational perspective for acute myeloid leukemia, including the development of selective and non-selective drugs.
RESUMO
Cytochrome P450s are the major family of enzymes responsible for the oxidative metabolism of pharmaceuticals and xenobiotics. CYP3A4 and CYP3A5 have been shown to have overlapping substrate and inhibitor profiles and their inhibition has been demonstrated to be involved in numerous pharmacokinetic drug-drug interactions. Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Imidazóis/química , Imidazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Citocromo P-450 CYP3A , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura MolecularRESUMO
Lung cancer is a malignant tumor with the highest morbidity and mortality rate worldwide, and it seriously endangers human health. In recent years, immunotherapy has been widely used in lung cancer and has achieved great benefits, especially the application of promoting antitumor immune defense. However, immune-related adverse events (irAEs) caused by immune checkpoint inhibitors have received increasing attention, which largely limits their use. We report the first case of new acute mastitis caused by anti-PD1 inhibitors due to lung adenocarcinoma. A 65-year-old female patient came to our hospital for treatment with cough and shortness of breath for one month. Chest CT showed that the malignant tumor in the lower lobe of the right lung with pleural effusion had metastasized to many places, and then pleural effusion was taken for pathological examination. Pathological examination indicated that the pleural fluid originated from lung adenocarcinoma. Subsequently, the patient received platinum-containing dual-agent chemotherapy (carboplatin and pemetrexed disodium) combined with immunotherapy (camrelizumab). During treatment, the patient developed known adverse events and unreported acute mastitis. After stopping camrelizumab, the patient's mastitis gradually improved. Our case shows that acute mastitis might be a new adverse event after the use of camrelizumab. Since this new adverse event has not been reported, we hope that oncology medical workers can obtain insight from our case and use it as a reference for the identification and management of irAEs.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Mastite , Derrame Pleural , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Therapeutic interventions with Rho kinase (ROCK) inhibitors may effectively treat several disorders such as hypertension, stroke, cancer, and glaucoma. Herein we disclose the optimization and biological evaluation of potent novel ROCK inhibitors based on substituted indole and 7-azaindole core scaffolds. Substitutions on the indole C3 position and on the indole NH and/or amide NH positions all yielded potent and selective ROCK inhibitors (25, 42, and 50). Improvement of aqueous solubility and tailoring of in vitro and in vivo DMPK properties could be achieved through these substitutions.