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1.
Eur Respir J ; 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680144

RESUMO

BACKGROUND: Signaling through platelet-derived growth factor receptor (PDGFR), colony stimulating factor 1 receptor (CSF1R), and c-KIT plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. METHODS: Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signaling were examined. PDGFR, CSF1R, and c-KIT immunohistochemistry (IHC) in rat and human PAH lung samples and miRNA analysis in the SU5416/H model were performed. RESULTS: Seralutinib potently inhibited PDGFRα/ß, c-KIT and CSF1R. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signaling, and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary hemodynamics and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary hemodynamics, restored lung BMPR2 protein levels, and decreased n-terminal prohormone of brain natriuretic peptide (NT-proBNP) more than imatinib. Quantitative IHC in human lung PAH samples demonstrated increased PDGFR, CSF1R, and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. CONCLUSIONS: Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary hemodynamics, reduction in NT-proBNP, reverse remodeling of pulmonary vascular pathology, and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.

2.
ACS Med Chem Lett ; 13(5): 812-818, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35586440

RESUMO

The toll-like receptors (TLRs) play key roles in activation of the innate immune system. Aberrant activation of TLR7 and TLR8 pathways can occur in the context of autoimmune disorders due to the elevated presence and recognition of self-RNA as activating ligands. Control of this unintended activation via inhibition of TLR7/8 signaling holds promise for the treatment of diseases such as psoriasis, arthritis, and lupus. Optimization of a 2-pyridinylindole series of compounds led to the identification of potent dual inhibitors of TLR7 and TLR8, which demonstrated good selectivity against TLR9 and other family members. The in vitro characterization and in vivo evaluation in rodent pharmacokinetic/pharmacodynamic and efficacy studies of BMS-905 is detailed, along with structural information obtained through X-ray cocrystallographic studies.

3.
J Immunol ; 207(1): 34-43, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34108258

RESUMO

Systemic lupus erythematosus (SLE) is associated with an IL-2-deficient state, with regulatory T cells (Tregs) showing diminished immune regulatory capacity. A low dose of IL-2 has shown encouraging clinical benefits in SLE patients; however, its clinical utility is limited because of the requirement of daily injections and the observation of increase in proinflammatory cytokines and in non-Tregs. We recently showed that a fusion protein of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, was effective in treating diabetes in NOD mice by selectively inducing Treg expansion. In this report, we show that mouse IL-2 (mIL-2)/CD25 at doses up to 0.5 mg/kg twice a week induced a robust Treg expansion without showing signs of increase in the numbers of NK, CD4+Foxp3-, or CD8+ T cells or significant increase in proinflammatory cytokines. In both NZB × NZW and MRL/lpr mice, mIL-2/CD25 at 0.2-0.4 mg/kg twice a week demonstrated efficacy in inducing Treg expansion, CD25 upregulation, and inhibiting lupus nephritis based on the levels of proteinuria, autoantibody titers, and kidney histology scores. mIL-2/CD25 was effective even when treatment was initiated at the time when NZB × NZW mice already showed signs of advanced disease. Furthermore, we show coadministration of prednisolone, which SLE patients commonly take, did not interfere with the ability of mIL-2/CD25 to expand Tregs. The prednisolone and mIL-2/CD25 combination treatment results in improvements in most of the efficacy readouts relative to either monotherapy alone. Taken together, our results support further evaluation of IL-2/CD25 in the clinic for treating immune-mediated diseases such as SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Linfócitos T Reguladores , Animais , Linfócitos T CD8-Positivos , Fatores de Transcrição Forkhead , Humanos , Interleucina-2 , Subunidade alfa de Receptor de Interleucina-2 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NOD
5.
J Med Chem ; 64(5): 2714-2724, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33591748

RESUMO

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.


Assuntos
Amidas/uso terapêutico , Hidrocarbonetos Cíclicos/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Psoríase/tratamento farmacológico , Amidas/química , Amidas/farmacocinética , Animais , Agonismo Inverso de Drogas , Feminino , Humanos , Hidrocarbonetos Cíclicos/química , Hidrocarbonetos Cíclicos/farmacocinética , Interleucina-23 , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Psoríase/induzido quimicamente , Ratos , Relação Estrutura-Atividade
6.
J Med Chem ; 64(3): 1454-1480, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33492963

RESUMO

Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.


Assuntos
Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Pró-Proteína Convertases/efeitos dos fármacos , Serina Endopeptidases/efeitos dos fármacos , Animais , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Biotransformação , Compostos Bicíclicos com Pontes/efeitos adversos , Líquido da Lavagem Broncoalveolar , Quimiotaxia de Leucócito/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
7.
J Immunother Cancer ; 9(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33408094

RESUMO

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. METHODS: Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. RESULTS: CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. CONCLUSION: CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Sarcoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacologia , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Sarcoma/imunologia , Sarcoma/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 63(23): 15050-15071, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33261314

RESUMO

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.


Assuntos
Naftiridinas/farmacologia , Quinolinas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Desenho de Fármacos , Feminino , Humanos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Estudo de Prova de Conceito , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
9.
ACS Med Chem Lett ; 11(12): 2510-2518, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33335675

RESUMO

Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.

10.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214829

RESUMO

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

11.
Bioorg Med Chem Lett ; 30(23): 127521, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882417

RESUMO

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.


Assuntos
Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Melanose/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sulfonas/uso terapêutico , Animais , Cristalografia por Raios X , Agonismo Inverso de Drogas , Feminino , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Interleucina-18 , Masculino , Melanose/induzido quimicamente , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacocinética
12.
ACS Med Chem Lett ; 11(9): 1751-1758, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32944143

RESUMO

The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.

13.
Bioorg Med Chem Lett ; 30(19): 127441, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736080

RESUMO

In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Animais , Cristalografia por Raios X , Descoberta de Drogas , Agonismo Inverso de Drogas , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/metabolismo
14.
Bioorg Med Chem Lett ; 30(17): 127392, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738966

RESUMO

A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.


Assuntos
Desenho de Fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pirrolidinas/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Agonismo Inverso de Drogas , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Receptor de Pregnano X/agonistas , Receptor de Pregnano X/metabolismo , Pirrolidinas/síntese química , Pirrolidinas/metabolismo , Relação Estrutura-Atividade
15.
ACS Med Chem Lett ; 11(6): 1221-1227, 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32551004

RESUMO

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

16.
J Med Chem ; 62(21): 9931-9946, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31638797

RESUMO

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.


Assuntos
Desenho de Fármacos , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Animais , Humanos , Células Jurkat , Camundongos , Modelos Moleculares , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
17.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacologia , Sulfonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Relação Estrutura-Atividade , Sulfonas/administração & dosagem , Sulfonas/química
18.
Sci Transl Med ; 11(502)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.


Assuntos
Autoimunidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , TYK2 Quinase/química , Animais , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos/farmacologia , Humanos , Interferon alfa-2/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores
19.
PLoS One ; 14(3): e0212670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913212

RESUMO

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.


Assuntos
Imunidade Celular , Vigilância Imunológica , Linfócitos/imunologia , Neoplasias Experimentais/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Linfócitos/patologia , Camundongos , Camundongos Mutantes , Neoplasias Experimentais/genética , Mutação Puntual , Microambiente Tumoral/genética
20.
ACS Med Chem Lett ; 10(3): 306-311, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891131

RESUMO

The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

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