SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103)

Histone deacetylase inhibitor MGCD0103 synergizes with gemcitabine in human pancreatic cells

“…Micromolar concentrations of MGCD0103 inhibited cell proliferation in a dose‐dependent manner, both on plastic as well as in a 3‐D clonogenic assay and the monolayer EC 50 values are consistent with those determined in previous in vitro studies. ( 22,24,25 ) However, most of the pancreatic cell lines and explants were not completely inhibited by MGCD0103 at concentrations comparable to levels attainable in clinical dosing regimens. Therefore, we next evaluated a dose range of MGCD0103 (including clinically achievable, submicromolar concentrations) in combination with gemcitabine in the tumor cell lines at three different treatment schedules (concurrent treatment, MGCD0103 pretreatment, and gemcitabine pretreatment) and found that, in all cases, MGCD0103 synergized with gemcitabine to induce cytotoxicity.…”

“…In vitro , MGCD0103 has potent antiproliferative activity against human tumor cell lines but not against normal cells at submicromolar to micromolar concentrations. ( 22–25 ) In pharmacological models, MGCD0103 showed significant antitumor activity at well‐tolerated doses in a variety of tumor types including colon, non‐small‐cell lung, pancreatic, and prostate cancer xenografts. Notably, drug was detected in the plasma up to 24 h post‐dose and for the first 8 h, plasma concentrations were at or above the EC 50 values needed to inhibit HDACs 1 and 2 in vitro .…”

Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit

“…Of the few reports of alternative ring systems to the pyrimidine ring in Mocetinostat, replacement has involved the use of only planar, fused rings that decrease the solubility, albeit affording compounds with therapeutic potential . Several analogues with planar rings in the capping group other than pyrimidine were less potent against HDAC1 and several cell lines than was Mocetinostat . SAR detail regarding the cap region of Mocetinostat congeners has been limited, especially in regard the potential influence of chirality; to our knowledge, there is only one publication describing chiral heterocyclic cap analogues of such aminoanilides …”

“…40 Several analogues with planar rings in the capping group other than pyrimidine were less potent against HDAC1 and several cell lines than was Mocetinostat. 41 SAR detail regarding the cap region of Mocetinostat congeners has been limited, especially in regard the potential influence of chirality; to our knowledge, there is only one publication describing chiral heterocyclic cap analogues of such aminoanilides. 34 Our previous study 34 showed that five-membered semisaturated ring systems such as imidazolin-4-one can be effective as a replacement for the pyrimidine ring in Mocetinostat and, promisingly, even in the absence of the terminal 3-pyridyl ring present in Mocetinostat. In the absence of a 3-pyridyl group, few analogues of Mocetinostat (in which the pyrimidine ring was retained) are potent HDAC inhibitors.…”

“…41 Since the carbonyl group of substituted imidazolin-4-ones rendered an adjacent chiral centre prone to racemisation, 34 1,2dihydroazole units, as pyrimidine replacements, became the focus of the present work. The greater saturation of most 1,2-dihydroazoles, and the greater solubility of compounds with unsaturated oxazoline and imidazoline rings compared to their pyrimidine counterparts were additional potential advantages in improving physicochemical properties.…”