RESUMO
OBJECTIVE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. METHODS: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. RESULTS: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. CONCLUSIONS: VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Orgânicos/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Benzamidas , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Interações Alimento-Droga , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/efeitos adversos , Compostos Orgânicos/farmacocinética , Pirazinas , SulfonamidasRESUMO
The tumor microenvironment plays a central role in cancer progression and metastasis. Within this environment, cancer cells respond to a host of signals including growth factors and chemotactic factors, as well as signals from adjacent cells, cells in the surrounding stroma, and signals from the extracellular matrix. Targeting the pathways that mediate many of these signals has been a major goal in the effort to develop therapeutics.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/fisiologia , Neoplasias/enzimologia , Neoplasias/fisiopatologia , Transdução de Sinais , Antineoplásicos/uso terapêutico , Progressão da Doença , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/genética , Humanos , Integrinas/fisiologia , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oligonucleotídeos Antissenso/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/genéticaRESUMO
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Conformação Molecular , Estrutura Molecular , Osteoporose/tratamento farmacológico , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
CP-673,451 is a potent inhibitor of platelet-derived growth factor beta-receptor (PDGFR-beta) kinase- and PDGF-BB-stimulated autophosphorylation of PDGFR-beta in cells (IC(50) = 1 nmol/L) being more than 450-fold selective for PDGFR-beta versus other angiogenic receptors (e.g., vascular endothelial growth factor receptor 2, TIE-2, and fibroblast growth factor receptor 2). Multiple models have been used to evaluate in vivo activity of CP-673,451 and to understand the pharmacology of PDGFR-beta inhibition and the effect on tumor growth. These models include an ex vivo measure of PDGFR-beta phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition. Inhibition of PDGFR-beta phosphorylation in tumors correlates with plasma and tumor levels of CP-673,451. A dose of 33 mg/kg was adequate to provide >50% inhibition of receptor for 4 hours corresponding to an EC(50) of 120 ng/mL in plasma at C(max). In a sponge angiogenesis model, CP-673,451 inhibited 70% of PDGF-BB-stimulated angiogenesis at a dose of 3 mg/kg (q.d. x 5, p.o., corresponding to 5.5 ng/mL at C(max)). The compound did not inhibit vascular endothelial growth factor- or basic fibroblast growth factor-induced angiogenesis at concentrations which inhibited tumor growth. The antitumor efficacy of CP-673,451 was evaluated in a number of human tumor xenografts grown s.c. in athymic mice, including H460 human lung carcinoma, Colo205 and LS174T human colon carcinomas, and U87MG human glioblastoma multiforme. Once-daily p.o. x 10 days dosing routinely inhibited tumor growth (ED(50) < or = 33 mg/kg). These data show that CP-673,451 is a pharmacologically selective PDGFR inhibitor, inhibits tumor PDGFR-beta phosphorylation, selectively inhibits PDGF-BB-stimulated angiogenesis in vivo, and causes significant tumor growth inhibition in multiple human xenograft models.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Becaplermina , Processos de Crescimento Celular/efeitos dos fármacos , Feminino , Glioblastoma/irrigação sanguínea , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/enzimologia , Paclitaxel/administração & dosagem , Fosforilação , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-sis , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Signaling through vascular endothelial growth factor (VEGF) receptors (VEGFRs) is a key pathway initiating endothelial cell proliferation and migration resulting in angiogenesis, a requirement for human tumor growth and metastasis. Abrogation of signaling through VEGFR by a variety of approaches has been demonstrated to inhibit angiogenesis and tumor growth. Small molecule inhibitors of VEGFR tyrosine kinase have been shown to inhibit angiogenesis, inhibit tumor growth, and prevent metastases. Our goal was to discover and characterize an p.o. active VEGFR-2 small molecule inhibitor. A novel isothiazole, CP-547,632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547,632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). These plasma concentrations correlated well with the observed concentrations of the compound necessary to inhibit VEGF-induced corneal angiogenesis in BALB/c mice. A sponge angiogenesis assay was used to directly compare the inhibitory activities of CP-547,632 against FGF receptor 2 or VEGFR-2; this compound potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. The antitumor efficacy of this agent was evaluated after once daily p.o. administration to athymic mice bearing human xenografts and resulted in as much as 85% tumor growth inhibition. CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies.
Assuntos
Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Nus , Células NIH 3T3 , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ureia/análogos & derivados , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Axitinib is an approved treatment for advanced renal cell carcinoma (RCC) after failure of 1 systemic therapy. PATIENTS AND METHODS: Long-term safety with single-agent axitinib was analyzed using pooled data from clinical trials in 672 previously treated patients with metastatic RCC (mRCC) and in 1304 patients with different advanced solid tumors. In all studies, except the phase I first-in-human, dose-finding study, the starting dose of oral axitinib was 5 mg twice daily continuously. Common long-term treatment-emergent adverse events (AEs) were identified in patients who received axitinib for ≥ 2 years, then evaluated in all patients, and assessed using interval, cumulative, and latency analyses. RESULTS: In all, 108 (16%) previously treated patients with mRCC received axitinib for ≥ 2 years. In interval analysis, most AEs occurred during the first 6 months of treatment, with rates stable or decreased over time; rates increased for proteinuria, peripheral edema, and increased blood creatinine. Common Grade ≥ 3 AE rates declined or plateaued over time, except for increased amylase and myocardial infarction. Results were similar in cumulative analysis in this population, and in interval and cumulative analyses in all patients with mRCC and those with advanced solid tumors. CONCLUSION: Declining or stable rates of most AEs support an acceptable long-term safety profile for axitinib in patients with mRCC. However, increases in the rates of some AEs warrant monitoring. This analysis is limited in that it was retrospective and included a relatively small patient population.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Axitinibe , Esquema de Medicação , Feminino , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Masculino , Metástase Neoplásica , Inibidores de Proteínas Quinases/administração & dosagem , Estudos RetrospectivosRESUMO
Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.
Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Hipertensão/induzido quimicamente , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Axitinibe , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , SorafenibeRESUMO
PURPOSE: PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. PATIENTS AND METHODS: Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. RESULTS: Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. CONCLUSION: The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 2 de Adesão Focal/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Austrália , Canadá , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Fluordesoxiglucose F18 , Quinase 1 de Adesão Focal/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Humanos , Masculino , Dose Máxima Tolerável , Midazolam/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico por imagem , Neoplasias/enzimologia , Neoplasias/patologia , Dinâmica não Linear , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Compostos Radiofarmacêuticos , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Estados UnidosRESUMO
Focal adhesion kinase (FAK) is a member of a family of non-receptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migration, proliferation, and survival. FAK expression is increased in many cancers, including breast and prostate cancer. Here we describe perturbation of adhesion-mediated signaling with a FAK inhibitor, PF-573,228. In vitro, this compound inhibited purified recombinant catalytic fragment of FAK with an IC(50) of 4 nM. In cultured cells, PF-573,228 inhibited FAK phosphorylation on Tyr(397) with an IC(50) of 30-100 nM. Treatment of cells with concentrations of PF-573,228 that significantly decreased FAK Tyr(397) phosphorylation failed to inhibit cell growth or induce apoptosis. In contrast, treatment with PF-573,228 inhibited both chemotactic and haptotactic migration concomitant with the inhibition of focal adhesion turnover. These studies show that PF-573,228 serves as a useful tool to dissect the functions of FAK in integrin-dependent signaling pathways in normal and cancer cells and forms the basis for the generation of compounds amenable for preclinical and patient trials.
Assuntos
Apoptose/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonas/química , Sulfonas/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Bone is accrued and maintained primarily through the coupled actions of bone-forming osteoblasts and bone-resorbing osteoclasts. Cumulative in vitro studies indicated that proline-rich tyrosine kinase 2 (PYK2) is a positive mediator of osteoclast function and activity. However, our investigation of PYK2-/- mice did not reveal evidence supporting an essential function for PYK2 in osteoclasts either in vivo or in culture. We find that PYK2-/- mice have high bone mass resulting from an unexpected increase in bone formation. Consistent with the in vivo findings, mouse bone marrow cultures show that PYK2 deficiency enhances differentiation and activity of osteoprogenitor cells, as does expressing a PYK2-specific short hairpin RNA or dominantly interfering proteins in human mesenchymal stem cells. Furthermore, the daily administration of a small-molecule PYK2 inhibitor increases bone formation and protects against bone loss in ovariectomized rats, an established preclinical model of postmenopausal osteoporosis. In summary, we find that PYK2 regulates the differentiation of early osteoprogenitor cells across species and that inhibitors of the PYK2 have potential as a bone anabolic approach for the treatment of osteoporosis.