UsiNg or disease-specific signatures of physiological processes AZD2171 such as requests, k Can small molecules in the database Connectivity Map, the positive or negative correlations are easily identifiable. 9, 10 May small molecules whose signature negatively correlated be useful to the Ph Undo phenotypes of specific diseases Dependent and help to make the rational selection of drug candidates for further investigation with specific disease signatures. On the other hand k Can compounds whose signature is clearly correlated with certain ph Phenotypic signatures to be able to get the Ph Inducing phenotype. Shown below draw examples where this strategy helped therapeutic candidates for the treatment of various cancers has identified, and compounds k Can modulate other physiological processes, such as hair.
Hepatocellular carcinoma Gef Invasion The identification of compounds that modulate Vaskul Re invasion hepatocellular carcinoma using a genetic signature invasion particularly 73 38 by comparing the Ph Genotype shows CHC Vaskul Re invasion of tumors obtained to 43 is missing in this Ph Genotype . 25 Input 47 and 26 up-regulated Fostamatinib genes in the Connectivity Map identified two small molecules with significant anti-correlation of the input signature. These agents are f, compatibility available to inhibit the invasive nature of both HCC HepG2 and PLC / PRF 5 to non-cytotoxic concentrations. Tracking experiments best Confirms this connection, the expression levels of several genes restore the invasion, adhesion version And angiogenesis.
Neuroblastoma, to identify therapeutic candidates for neuroblastoma, was a meta-analysis integrated gene copy prim using the expression profiles of neuroblastoma tumors of 146 Ren and normal fetal neuroblasts build a list of the 132 genes of tumor-specific. Provided 26 Five of six compounds of the first connectivity map could clearly reduced Zelllebensf Conductivity in five neuroblastoma contain a HSP90 inhibitor compounds, a HDAC inhibitor, an inhibitor of mTOR and phenotriazene. Although the toxicity of these compounds are not limited to neuroblastoma, this approach provides a rational basis for the selection of candidates for therapeutic clinical trials of neuroblastoma. Acute Stem cell myeloid leukemia Mie Le r the cancer stem cells in leukemia has been well characterized. 27 selective toxicity t Against AML stem cells was observed in vitro with parthenolide.
28, 29 The F These agents AML SC ability to t Th to its F Ability to inhibit NF B attributed κ signals simultaneously and the induction of oxidative stress. PTL 28, s selective toxicity t Against SC AML versus normal hours Hematopoietic stem Etic Preferences shore cells, And as a tool used to create new connections, identify the induction of the death AML SC. With the acquisition of 30 signatures of gene expression of CD34 AML treated with PTL and compared to untreated cells, 150 signature genes can be used to bring the database and GEO map connectivities Check for inducing agents Similar signatures. Besides known for its anti-AML agents SC, celastrol were identified in both searches in databases and three other compounds H Min EST and gedunin from the GEO database search identified.