While the meiotic transcriptional program and pre-meiotic DNA synthesis were largely unchanged, the meiotic divisions were strongly inhibited. Finally, we found that the neo1D/NEO1 heterozygous strain is highly sensitized to TA in sporulating cultures. Neo1 is involved in intracellular membranetrafficking, protein sorting and vacuole biogenesis. Temperaturesensitive mutants of neo1 have been shown to exhibit fragmented and hyper-acidic vacuoles. Thus, the observed sensitivity of the neo1D/NEO1 strain to TA may be due to decreased vacuolar pH of the strain, resulting in elevated trapping of TA in the vacuole and increased obstruction of autophagy. Additional work is needed to elucidate the precise mechanism by which TA suppresses spore formation and to determine to what extent autophagic processes are involved. Since all 12 drugs identified here are positively charged amphiphiles it is tempting to speculate that they have a common mechanism of Niraparib action. Further experimentation will however be necessary to test this hypothesis. In summary, we have found that cationic amphiphilic drugs are potent inhibitors of yeast sporulation. The data presented here open up an important avenue to study metabolic and membrane processes required for sporulation in yeast. Sphingosine kinasescatalyze the 
phosphorylation of sphingosine to generate sphingosine-1-phosphate. Ceramide and sphingosine, which are upstream of SKs, are pro-apoptotic, while S1P PF-4217903 promotes proliferation, inflammation and migration. Therefore, SKs balance the levels of S1P and ceramide, and so are being increasingly recognized as potential targets for anticancer drugs. However, because two SK isoenzymes exist, it is important to determine if SK1, SK2 or both should be targeted for cancer chemotherapy. The SKs are encoded by distinct genes with 45% identity and 80% similarity in their amino acid sequences, and share five conserved domains. Although no crystal structure is available, the SKs share homology with the catalytic domain of diacylglycerolkinase, for which a crystal structure has been published. Several topologic and functional differences between SK1 and SK2 have been described. For example, SK1 is a cytosolic protein that migrates to the plasma membrane upon activation by several stimuli. Up- and down-regulation of SK1 expression results in pro- and anti-cancer effects, respectively. Conversely, SK2 contains a nuclear localization signal, which results in both nuclear and cytosolic protein when overexpressed. The role of SK2 in cell proliferation has been somewhat unclear. On one hand, SK2 contains a pro-apoptotic BH3 domain which promotes apoptosis when this protein is overexpressed. Alternately, down-regulation of SK2 inhibits the proliferation of tumor cells, and the growth of SK2deficient xenografts in mice is significantly delayed. Although several small molecule inhibitors of SKs have been described, detailed characterizations of their pharmacology, particularly their selectivity against human SK1 and SK2, have not been completed. The first known SK inhibitors were sphingosine analogues such as N,N-dimethyl-D-erythro-sphingosinethat block the activities of both SK1 and SK2 by competing with the natural substrate sphingosine. DMS is reported to inhibit tumor growth and to induce cancer cell apoptosis; however, DMS also inhibits PKC and other kinases, and therefore is not considered to be an SK-specific inhibitor. A few compounds have been described as SK1selective inhibitors, including SK1-I which reduces the growth rate of glioblastoma and AML xenografts,, and SKI-178 which inhibits the proliferation of a variety of cancer cell lines.