RESUMO
Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Linfócitos B , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular TumoralRESUMO
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
Assuntos
Antineoplásicos/química , Naftiridinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Quinolonas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Naftiridinas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Quinolonas/metabolismo , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with â¼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.
Assuntos
Artrite Reumatoide , Fosfatidilinositol 3-Quinases , Artrite Reumatoide/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-AtividadeRESUMO
The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Descoberta de Drogas , Administração Oral , Animais , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacocinética , Ensaios Clínicos Fase I como Assunto , Humanos , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.