AID	Name	Type	Comment
2386	Probe Development Summary for Inhibitors of Bloom's syndrome helicase (BLM)	summary	Summary AID

Survival of cells and the faithful propagation of the genome depend on elaborate mechanisms of detecting and repairing DNA damage. Treatment of advanced cancer relies on radiation therapy or chemotherapy, which kill cancer cells by causing extensive DNA damage. It is often found, that cancer cells develop resistance to therapy through enhanced activity of DNA repair functions; this has led to an increased interest in developing drugs that interfere with DNA repair, which could sensitize cancer cells to conventional therapy. Bloom syndrome helicase (BLM), is important in resolving abnormal DNA structures formed during replication or homologous recombination. Shutting down the expression of BLM leads to chromosomal instability and higher radiation sensitivity in cultured cells. After the completion of a qHTS campaign, secondary assays, and rounds of medicinal chemistry, a compound was identified to be further characterized through in vitro ADME assays.

The stability of the lead compound in PBS buffer is tested because this parameter has a significant impact on many ADME-concerned properties of drugs, such as uptake, distribution, transport, and eventually bioavailability.

NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Production Centers Network [MLPCN]

MLSCN Grant: MH087284
PI Name: Dr. Opher Gileadi, Structural Genomics Consortium, University of Oxford, UK

2uM of compound is incubated in PBS buffer at pH 7; the reference compound is procaine. Compounds are incubated at 37 deg C for the pre-determined time periods and the when aliquots are removed. Samples are analyzed with LC-MS/MS.

Compounds are "active" if percent remaining after 48 h is equal or more than 90%; "inactive" if percent remaining after 48 h is less than 90%.

PUBCHEM_ACTIVITY_SCORE is the closets whole number of percent remaining after 48 hours.

Grant Number: MH087284