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1.
Nat Commun ; 15(1): 5842, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38992037

RESUMO

Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy, and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro, in vivo (in female mice), and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors, with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore, STINGa ADCs induce type III interferons, which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs.


Assuntos
Imunidade Inata , Imunoconjugados , Interferons , Proteínas de Membrana , Animais , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Imunidade Inata/efeitos dos fármacos , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Imunoconjugados/farmacologia , Imunoconjugados/administração & dosagem , Interferons/metabolismo , Interferon lambda , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Interferon Tipo I/imunologia , Citocinas/metabolismo , Células Mieloides/imunologia , Células Mieloides/efeitos dos fármacos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Receptores de IgG/agonistas , Receptores de IgG/metabolismo , Receptores de IgG/imunologia
2.
Mol Cancer Ther ; 23(4): 541-551, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38354416

RESUMO

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Ratos , Animais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Alquilantes , Neoplasias/tratamento farmacológico , DNA/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia
3.
Mol Cancer Ther ; 23(1): 84-91, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37774393

RESUMO

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.


Assuntos
Imunoconjugados , Humanos , Imunoconjugados/química , Ensaios Antitumorais Modelo de Xenoenxerto , Trastuzumab/farmacologia , Trastuzumab/química , Receptor ErbB-2/metabolismo , Cisteína
4.
J Med Chem ; 66(15): 10715-10733, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37486969

RESUMO

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/farmacocinética , Anticorpos Monoclonais , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico
5.
Mol Cancer Ther ; 22(9): 999-1012, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37294948

RESUMO

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Anticorpos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Bioorg Med Chem Lett ; 72: 128876, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35788036

RESUMO

Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10-11-10-8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads.


Assuntos
Antineoplásicos , Imunoconjugados , Animais , Antineoplásicos/farmacologia , Benzodiazepinas , Linhagem Celular Tumoral , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos , Nylons/farmacologia , Pirróis , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cancer Ther ; 20(5): 885-895, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722857

RESUMO

After significant effort over the last 30 years, antibody-drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs have been approved by the FDA to date, with additional ADCs in late stages of development. Here, we introduce dolaflexin, a novel ADC technology that overcomes key limitations of the most common ADC platforms with two key features: a higher drug-to-antibody ratio and a novel auristatin with a controlled bystander effect. The novel, cell permeable payload, auristatin F-hydroxypropylamide, undergoes metabolic conversion to the highly potent, but less cell permeable auristatin F to balance the bystander effect through drug trapping within target cells. We conducted studies in mice, rats, and cynomolgus monkeys to complement in vitro characterization and contrasted the performance of dolaflexin with regard to antitumor activity, pharmacokinetic properties, and safety in comparison with the ADC platform utilized in the approved ADC ado-trastuzumab emtansine (T-DM1). A HER2-targeted dolaflexin ADC was shown to have a much lower threshold of antigen expression for potent cell killing in vitro, was effective in vivo in tumors with low HER2 expression, and induced tumor regressions in a xenograft model that is resistant to T-DM1.


Assuntos
Imunoconjugados/uso terapêutico , Oligopeptídeos/uso terapêutico , Polímeros/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Imunoconjugados/farmacologia , Camundongos , Camundongos SCID , Oligopeptídeos/farmacologia , Polímeros/farmacologia
8.
Mol Cancer Ther ; 20(5): 896-905, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722858

RESUMO

Target selection for antibody-drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10-15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.


Assuntos
Antígenos de Neoplasias/metabolismo , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Polímeros/uso terapêutico , Animais , Feminino , Humanos , Imunoconjugados/farmacologia , Camundongos , Camundongos SCID , Oligopeptídeos/farmacologia , Polímeros/farmacologia
9.
Pharmacol Ther ; 181: 126-142, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28757155

RESUMO

Breast cancer is a heterogeneous group of malignancies with a spectrum of molecular subtypes, pathologies and outcomes that together comprise the most common non-cutaneous cancer in women. Currently, over 80% of breast cancer patients are diagnosed at relatively early stages of disease where there are encouraging data on outcomes and long term survival. However, there is currently no curative option for those patients with metastatic disease and there is a substantial medical need to identify effective and safe treatment options for these patients. One approach to improve cancer therapy is by designing therapeutics directed against targets with differential levels of expression on malignant versus normal cells with the goal of improving tumor selectivity and reducing damage to normal tissues. Antibody drug conjugates (ADCs) are a rapidly evolving therapeutic class that exploits the target-selectivity of monoclonal antibodies (MAbs) to deliver cytotoxic drugs to antigen-expressing cells (Lambert & Morris, 2017; Senter, 2009; Thomas, Teicher, & Hassan, 2016; Trail, 2013). The regulatory approval of ADCs for both hematologic malignancies (brentuximab vedotin) (Younes et al., 2010) and solid tumors (ado-trastuzumab emtansine) (Amiri-Kordestani et al., 2014; Verma et al., 2012) clearly demonstrates the clinical potential of ADCs. This review will focus on targets under consideration for breast cancer directed ADCs and on the technology modifications being considered to improve ADC efficacy and safety.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Imunoconjugados/uso terapêutico , Terapia de Alvo Molecular/métodos , Humanos
10.
Cancer Res ; 75(16): 3365-72, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26113086

RESUMO

Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.


Assuntos
Imunoconjugados/química , Imunoconjugados/farmacologia , Polímeros/química , Alcaloides de Vinca/química , Acetais/química , Animais , Antígenos CD20/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoconjugados/farmacocinética , Células MCF-7 , Camundongos SCID , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptor ErbB-2/imunologia , Rituximab/química , Rituximab/imunologia , Fatores de Tempo , Trastuzumab/química , Trastuzumab/imunologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Clin Cancer Res ; 18(9): 2591-602, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22392910

RESUMO

PURPOSE: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. EXPERIMENTAL DESIGN: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography-tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. RESULTS: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. CONCLUSIONS: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11.


Assuntos
Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Polímeros/farmacologia , Polímeros/farmacocinética , Acetais , Animais , Camptotecina/farmacocinética , Camptotecina/farmacologia , Cromatografia Líquida , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Espectrometria de Massas em Tandem , Distribuição Tecidual , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bioorg Med Chem Lett ; 21(11): 3354-7, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21531136

RESUMO

We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystometry models of urinary incontinence after intravenous administration.


Assuntos
Naftóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Incontinência Urinária/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Concentração Inibidora 50 , Estrutura Molecular , Naftóis/síntese química , Naftóis/uso terapêutico , Nutrição Parenteral , Ratos , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 17(15): 4378-81, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17574417

RESUMO

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 17(10): 2869-73, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17400452

RESUMO

Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.


Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Quinolinas/farmacologia , Desenho de Fármacos , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
15.
Nat Rev Drug Discov ; 5(10): 835-44, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17016424

RESUMO

Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Benzenossulfonatos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos como Assunto , Técnicas de Química Combinatória , Humanos , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sorafenibe , Quinases raf/antagonistas & inibidores
16.
Br J Pharmacol ; 145(2): 178-92, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15753951

RESUMO

1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kappaB). 3 NF-kappaB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-beta. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-beta inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Oxazinas/farmacologia , Pneumonia/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/biossíntese , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Edema/prevenção & controle , Feminino , Humanos , Quinase I-kappa B , Proteínas I-kappa B/metabolismo , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Oxazinas/efeitos adversos , Oxazinas/farmacocinética , Fosforilação , Pneumonia/imunologia , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
17.
Curr Opin Drug Discov Devel ; 7(5): 600-16, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15503863

RESUMO

With two compounds on the market (Gleevec and Iressa), and a number of drug candidates in late-stage clinical trials, small-molecule kinase inhibitors hold great potential as novel therapies for cancer and inflammatory disorders. Inhibitors from the urea class were first reported in 1996 and have emerged as an important compound class for medicinal chemists due to their unique binding mode and kinase inhibition profile. Currently, five members of this class are undergoing clinical trials, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), BAY-43-9006 (Bayer AG/Onyx Pharmaceuticals Inc), CP-547632 (Pfizer Inc), MLN-518 (Millennium Pharmaceuticals Inc) and KRN-951 (Kirin Brewery Co Ltd). This review focuses on the most recent developments in the discovery of urea-based protein kinase inhibitors.


Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Ureia/análogos & derivados , Química Farmacêutica/tendências , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Ureia/química , Ureia/uso terapêutico
18.
Bioorg Med Chem Lett ; 14(15): 4013-7, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225717

RESUMO

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Inibidores Enzimáticos/química , Humanos , Quinase I-kappa B , Cinética , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 14(15): 4019-22, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225718

RESUMO

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).


Assuntos
Anti-Inflamatórios/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Edema/prevenção & controle , Humanos , Quinase I-kappa B , Cinética , Camundongos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 14(3): 783-6, 2004 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-14741289

RESUMO

Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.


Assuntos
Inibidores Enzimáticos/farmacologia , MAP Quinase Quinase Quinase 1 , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Amidas/síntese química , Amidas/farmacologia , Baculoviridae/genética , Inibidores Enzimáticos/síntese química , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Proteínas Recombinantes/antagonistas & inibidores , Solubilidade , Relação Estrutura-Atividade , Ureia/síntese química
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