Identification of small molecules targeting KRAS effectors

National Center For Advancing Translational Sciences

Investigators

Abstract

Thus far we have screened 385,000+ compounds for their ability to modulator KRAS binding to effectors. 31,000+ were tested against KRAS-Raf1, and 353,000+ compounds (mostly from the NCI natural products collections) were tested against KRAS-NF1. On the KRas-RAF1 we identified 54 initial hits that were validated in cherry-pick assays. These compounds were transferred to our collaborators at NCI for biophysical testing that is in process. On the KRAS-NF1 track we identified 10 hits from in-house libraries and 91 crude fractions from the NCI natural products collections with potential stabilizing interactions. We have a lead compound with apparent molecular glue activity that has been validated in SPR by our collaborators at NCI. The natural products are in the processing of being sub-fractionated, identified, and characterized. We have tested 6 of these purified compounds so far with no confirmed glue behavior.