Most common forms of leukemia are causally linked to the expression of the Philadelphia chromosome, which leads to production of the uncontrollably active tyrosine kinase Bcr-Abl, which in turn allows for overproduction of leukocytes, a hallmark of leukemia. Patients carrying the Philadelphia chromosome now take inhibitors of Bcr-Abl, such as Gleevec�, to curb the effects of the disease or even to prevent its onset. Mutations in Bcr-Abl can unfortunately confer drug resistance, so 2nd generation analogs that are effective against many mutant forms have been advanced.  In an alternative but perhaps complimentary approach, we have targeted an upstream regulator of native Abl (and also of mutant Bcr-Abl): the allosteric activator protein Rin1. Leukocyte proliferation is halted in the absence of Rin1 activation. Here we present early results of an uHTS-derived effort, within the NIH's Molecular Libraries Probe Center Network (MLPCN), to find small molecules that block the Rin1-Abl interaction.  We show results of a screening campaign using the NIH collection (~360,000 small molecules), confirmation of hits, selection of multiple lead series for possible chemistry follow-up, and early SAR to augment potency and verify mechanism of action.

Efforts toward finding small molecule molecular probes to test a new approach to leukemia treatment: Blocking the Rin1/Abl protein-protein interaction

245th National Meeting (2013)

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