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1.
Eur J Haematol ; 102(2): 163-173, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30347469

RESUMO

OBJECTIVES: Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. METHODS: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty-four patients were treated with domatinostat. RESULTS: No formal maximum tolerated dose (MTD) was determined. One dose-limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment-related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. CONCLUSION: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.


Assuntos
Benzamidas/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Resultado do Tratamento
2.
Bioorg Med Chem Lett ; 19(5): 1349-56, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19211246

RESUMO

Starting with a hit from vHTS attained by a docking procedure of virtual compounds into ATP pockets of different kinases applying the 4SCan technology, variations of the adenine mimic resulted in the identification of promising scaffolds, giving rise to in vitro IC(50) values in the nanomolar range on different kinases down to 63nM.


Assuntos
Benzotiazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Benzotiazóis/metabolismo , Sítios de Ligação/fisiologia , Inibidores de Proteínas Quinases/metabolismo
5.
PLoS One ; 8(11): e79594, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24324550

RESUMO

Microtubule inhibitors are invaluable tools in cancer chemotherapy: taxanes and vinca alkaloids have been successfully used in the clinic over the past thirty years against a broad range of tumors. However, two factors have limited the effectiveness of microtubule inhibitors: toxicity and resistance. In particular, the latter is highly unpredictable, variable from patient to patient and is believed to be the cause of treatment failure in most cases of metastatic cancers. For these reasons, there is an increasing demand for new microtubule inhibitors that can overcome resistance mechanisms and that, at the same time, have reduced side effects. Here we present a novel microtubule inhibitor, 4SC-207, which shows strong anti-proliferative activity in a large panel of tumor cell lines with an average GI50 of 11 nM. In particular, 4SC-207 is active in multi-drug resistant cell lines, such as HCT-15 and ACHN, suggesting that it is a poor substrate for drug efflux pumps. 4SC-207 inhibits microtubule growth in vitro and in vivo and promotes, in a dose dependent manner, a mitotic delay/arrest, followed by apoptosis or aberrant divisions due to chromosome alignment defects and formation of multi-polar spindles. Furthermore, preliminary data from preclinical studies suggest low propensity towards bone marrow toxicities at concentrations that inhibit tumor growth in paclitaxel-resistant xenograft models. In summary, our results suggest that 4SC-207 may be a potential anti-cancer agent.


Assuntos
Microtúbulos/efeitos dos fármacos , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Imunofluorescência , Células HeLa , Humanos , Tubulina (Proteína)/metabolismo
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