RESUMO
The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced γH2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and γH2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%~100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.
Assuntos
Antineoplásicos/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Haplorrinos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Camundongos , Neoplasias/enzimologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Ratos , Temozolomida , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In the traditional framework of multivariate spectroscopic calibration, the most popular method, partial least squares (PLS), shrinks the regression coefficients based on the information of training sample concentrations. Motivated by the concept of parallel calibration, the second direction for shrinkage of regression coefficients, the direction towards unknown sample spectra is investigated in this paper. A different multivariate calibration method, parallel calibration model based on partial least squares, PCPLS is proposed. With both theoretical support and analysis of some real data sets, it is demonstrated that the second shrinkage direction is at least as natural and necessary as the traditional one. An interesting difference of the proposed method from traditional methods is the involvement of unknown sample spectra and consideration of their error in the training process. Some new related problems and potential applications of this method are also briefly discussed.
Assuntos
Análise Espectral/métodos , Calibragem , Análise dos Mínimos Quadrados , Método de Monte Carlo , Análise Multivariada , Análise de Regressão , Análise Espectral/normasRESUMO
The manganacarborane dianion in [N(PPh(3))(2)][NEt(4)][1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(9)] (1b) reacts with cationic transition metal-ligand fragments to give products in which the electrophilic metal groups (M') are exo-polyhedrally attached to the {closo-1,2-MnCB(9)} cage system via three-center two-electron B-H --> M' linkages and generally also by Mn-M' bonds. With {Cu(PPh(3))}(+), the Cu-Mn-Cu trimetallic species [1,6-{Cu(PPh(3))}-1,7-{Cu(PPh(3))}-6,7-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (3a) is formed, whereas reactions with {M'(dppe)}(2+) (M' = Ni, Pd; dppe = Ph(2)PCH(2)CH(2)PPh(2)) give [1,3-{Ni(dppe)}-3-(mu-H)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(8)] (5a) and [1,3,6-{Pd(dppe)}-3,6-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (5b), both of which contain M'-Mn bonds. The latter reaction with M' = Pt affords [3,6-{Pt(dppe)}-3,6-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (6), which lacks a Pt-Mn connectivity. Compound 6 itself spontaneously converts to [1-Ph-2,2,2-(CO)(3)-8,8-(dppe)-hypercloso-8,2,1-PtMnCB(9)H(9)] (7b) and thence to [3,6,7-{Mn(CO)(3)}-3,7-(mu-H)(2)-1-Ph-6,6-(dppe)-closo-6,1-PtCB(8)H(6)] (8). This sequence occurs via initial insertion of the {Pt(dppe)} unit and then extrusion of {Mn(CO)(3)} and one {BH} vertex. In the presence of alcohols ROH, compound 6 is transformed to the 7-OR substituted analogues of 7b. X-ray diffraction studies were essential in elucidating the structures encountered in compounds 5-8 and hence in understanding their behavior.