Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute(SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: X01 MH083230-01
Assay Provider: Dr. Dmitri Rozanov, Sanford-Burnham Medical Research Institute(SBMRI, San Diego, CA

Cytotoxic chemotherapy induces apoptosis via a pathway involving mitochondria, sometimes referred to as the "intrinsic pathway." An acquired resistance to anticancer drugs commonly results from the accumulation of defects in components of the mitochondrial pathway for apoptosis. Discovering and identifying alternative pathways for triggering tumor cells apoptosis offer hope for more effective outcomes. Members of the Tumor Necrosis Factor (TNF) family of "death receptors" induce apoptosis via a direct mechanism that proceeds without involving mitochondria - referred to as the "extrinsic pathway." These cytokine receptors are frequently employed by immune cells to attack tumors. The PI believes that a successful strategy can be implemented by identifying specific chemicals that will selectively potentiate the therapeutic effects of the Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL). Unlike other TNF-family members, TRAIL is a powerful and safe cancer therapeutic because it can induce broad spectrum apoptosis of different cancer cells but not normal cells. Unfortunately many cancer cells have proven to be resistant to TRAIL alone.

The goal of this project is to screen for chemical compounds that selectively sensitize tumor cells to the extrinsic apoptosis pathway activated by TRAIL, without affecting other cell death pathways and normal cells. These compounds would provide useful research tools for interrogating mechanisms of TRAIL-resistance, and they also might serve as the basis for future drug development programs to create a new generation of non-toxic anticancer drugs that restore sensitivity to endogenous pathways used by the immune system for eradicating tumors.

AIDs 1443,1447, 1624, 1745, 1746, 1747,1748, 1752,1754, 1755, 1756 and 1765 were carried out to select probe molecules SID-57287667 and SID-57309194, CID 3380841(ML100).


References:
Bodmer JL, Meier P, Tschopp J, Schneider P. Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL. J Biol Chem 2000, 275:20632-7.

Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D, Ashkenazi A. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001, 7:383-5.

Singh TR, Shankar S, Chen X, Asim M, Srivastava RK. Synergistic interactions of chemotherapeutic drugs and tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand on apoptosis and on regression of breast carcinoma in vivo. Cancer Res 2003, 63:5390-400

Greil R, Anether G, Johrer K, Tinhofer I. Tracking death dealing by Fas and TRAIL in lymphatic neoplastic disorders: pathways, targets, and therapeutic tools. J Leukoc Biol 2003, 74:311-30.

Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H. Nature's TRAIL-on a path to cancer immunotherapy. Immunity 2003, 18:1-6.

Please see pertinent AIDs: 1443,1447, 1624, 1745, 1746, 1747,1748, 1752,1754, 1755, 1756 and 1765

Probe molecules are defined as the positives of this assay and assigned a score of 100. Molecules SID-57287667 and SID-57309194 have been identfied as probe molecules.

Grant Number: X01 MH083230-01