RESUMEN
Aim: FP-208 is a novel and effective small-molecule inhibitor blocking the mammalian target of rapamycin complex-1/mammalian target of rapamycin complex-2/PI3Ka. To investigate the pharmacokinetic profile of FP-208, a rapid and reliable analytical method was needed to be established to determine FP-208 in the plasma of patients with solid tumors. Materials & methods: FP208 was separated on a charged surface hybrid (CSH) C18 column (2.1 mm × 50 mm, 1.7 µm) after the plasma samples were purified using a protein precipitation method. Detection was performed on an AB Sciex 5500 mass spectrometer in the positive electrospray ionization mode. The established method was validated according to the bioanalytical guidelines. Conclusion: For the first time, the developed and validated method was successfully applied in the first-in-human study for FP-208 in patients with solid tumors after oral administration (Number: CTR20180683).
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Imidazoles/sangre , Inhibidores de Proteínas Quinasas/sangre , Bibliotecas de Moléculas Pequeñas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
A series of N'(1),N'(3)-dialkyl-N'(1),N'(3)-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure-activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Descubrimiento de Drogas , Hidrazinas/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Ratones , Ratones Desnudos , Modelos Moleculares , Conformación Molecular , Neoplasias Experimentales/patología , Paclitaxel/química , Paclitaxel/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Overall benefits of EGFR-TKIs are limited because these treatments are largely only for adenocarcinoma (ADC) with EGFR activating mutation. The treatments also usually lead to development of resistances. We have established a panel of patient-derived xenografts (PDXs) from treatment naïve Asian NSCLC patients, including those containing "classic" EGFR activating mutations. Some of these EGFR-mutated PDXs do not respond to erlotinib: LU1868 containing L858R/T790M mutations, and LU0858 having L858R mutation as well as c-MET gene amplification, both squamous cell carcinoma (SCC). Treatment of LU0858 with crizotinib, a small molecule inhibitor for ALK and c-MET, inhibited tumor growth and c-MET activity. Combination of erlotinib and crizotinib caused complete response, indicating the activation of both EGFR and c-MET promote its growth/survival. LU2503 and LU1901, both with wild-type EGFR and c-MET gene amplification, showed complete response to crizotinib alone, suggesting that c-MET gene amplification, not EGFR signaling, is the main oncogenic driver. Interestingly, LU1868 with the EGFR L858R/T790M, but without c-met amplification, had a complete response to cetuximab. Our data offer novel practical approaches to overcome the two most common resistances to EGFR-TKIs seen in the clinic using marketed target therapies.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/genética , Cetuximab , Crizotinib , Análisis Mutacional de ADN , Receptores ErbB/genética , Clorhidrato de Erlotinib , Femenino , Amplificación de Genes , Humanos , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Mutación Puntual , Proteínas Proto-Oncogénicas c-met/genética , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Quinazolinas/uso terapéutico , Transcriptoma , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 µm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Triazoles/farmacología , Animales , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Benzoquinonas/efectos adversos , Benzoquinonas/farmacología , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Cristalografía por Rayos X , Femenino , Células HL-60 , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiología , Humanos , Células K562 , Lactamas Macrocíclicas/efectos adversos , Lactamas Macrocíclicas/farmacología , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias/metabolismo , Neoplasias/patología , Conejos , Ratas , Ratas Sprague-Dawley , Triazoles/efectos adversos , Triazoles/química , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Elesclomol (formerly STA-4783) is a novel small molecule undergoing clinical evaluation in a pivotal phase III melanoma trial (SYMMETRY). In a phase II randomized, double-blinded, controlled, multi-center trial in 81 patients with stage IV metastatic melanoma, treatment with elesclomol plus paclitaxel showed a statistically significant doubling of progression-free survival time compared with treatment with paclitaxel alone. Although elesclomol displays significant therapeutic activity in the clinic, the mechanism underlying its anticancer activity has not been defined previously. Here, we show that elesclomol induces apoptosis in cancer cells through the induction of oxidative stress. Treatment of cancer cells in vitro with elesclomol resulted in the rapid generation of reactive oxygen species (ROS) and the induction of a transcriptional gene profile characteristic of an oxidative stress response. Inhibition of oxidative stress by the antioxidant N-acetylcysteine blocked the induction of gene transcription by elesclomol. In addition, N-acetylcysteine blocked drug-induced apoptosis, indicating that ROS generation is the primary mechanism responsible for the proapoptotic activity of elesclomol. Excessive ROS production and elevated levels of oxidative stress are critical biochemical alterations that contribute to cancer cell growth. Thus, the induction of oxidative stress by elesclomol exploits this unique characteristic of cancer cells by increasing ROS levels beyond a threshold that triggers cell death.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Hidrazinas/farmacología , Estrés Oxidativo , Secuencia de Bases , Línea Celular Tumoral , Cartilla de ADN , Perfilación de la Expresión Génica , Humanos , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
OBJECTIVE: Mutations of the receptor tyrosine kinase Kit occur in several human and canine cancers. While Kit inhibitors have activity in the clinical setting, they possess variable efficacy against particular forms of mutant Kit and drug resistance often develops over time. Inhibitors of heat shock protein 90 (HSP90), a chaperone for which Kit is a client protein, have demonstrated activity against human cancers and evidence suggests they downregulate several mutated and imatinib-resistant forms of Kit. The purpose of this study was to evaluate a novel HSP90 inhibitor, STA-9090, against wild-type (WT) and mutant Kit in canine bone marrow-derived cultured mast cells (BMCMCs), malignant mast cell lines, and fresh malignant mast cells. MATERIALS AND METHODS: BMCMCs, cell lines, and fresh malignant mast cells were treated with STA-9090, 17-AAG, and SU11654 and evaluated for loss in cell viability, cell death, alterations in HSP90 and Kit expression/signaling, and Kit mutation. STA-9090 activity was tested in a canine mastocytoma xenograft model. RESULTS: Treatment of BMCMCs, cell lines, and fresh malignant cells with STA-9090 induced growth inhibition, apoptosis that was caspase-3/7-dependent, and downregulation of phospho/total Kit and Akt, but not extracellular signal-regulated kinase (ERK) or phosphoinositide-3 kinase (PI-3K). Loss of Kit cell-surface expression was also observed. Furthermore, STA-9090 exhibited superior activity to 17-AAG and SU11654, and was effective against malignant mast cells expressing either WT or mutant Kit. Lastly, STA-9090 inhibited tumor growth in a canine mastocytoma mouse xenograft model. CONCLUSIONS: STA-9090 exhibits broad activity against mast cells expressing WT or mutant Kit, suggesting it may be an effective agent in the clinical setting against mast cell malignancies.