Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotypeselective HDAC inhibitor. We have developed an isotypeselective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759 -68]

Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.

In recent years, the phenomenon of global warming and its implications for the future of the human race have been intensively studied. In contrast, few quantitative studies have been attempted on the notable effects of past climatic changes upon human societies. This study explored the relationship between climatic change and war in China by comparing high-resolution paleoclimatic reconstructions with known war incidences in China in the last millennium. War frequencies showed a cyclic pattern that closely followed the global paleo-temperature changes. Strong and significant correlations were found between climatic change, war occurrence, harvest level, population size and dynastic transition. During cold phases, China suffered more often from frequent wars, population decline and dynastic changes. The quantitative analyses suggested that the reduction of thermal energy input during a cold phase would lower the land carrying capacity in the traditional agrarian society, and the population size, with significant accretions accrued in the previous warm phase, could not be sustained by the shrinking resource base. The stressed human-nature relationship generated a 'push force', leading to more frequent wars between states, regions and tribes, which could lead to the collapse of dynasties and collapses of human population size. War frequencies varied according to geographical locations (North, Central and South China) due to spatial variations in the physical environment and hence differential response to climatic change. Moreover, war occurrences demonstrated an obvious time lag after an episode of temperature fall, and the three geographical regions experienced different length of time lags. This research also shows that human population increases and collapses were correlated with the climatic phases and the social instabilities that were induced by climate changes during the last millennium. The findings proposed a new interpretation of human-nature relationship in the past, with implications for the impacts of anomalous global warming on future human conflicts.

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.

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