Novel Small Molecule Inhibitors Of Oncogenic Shp2 Variants The webinar focuses on utilizing an incell pulse to characterize small molecule cellular target engagement. as an example, a case study on characterization o. The discovery of small molecules inhibitors that target oncogenic forms of shp2 phosphatase holds great therapeutic promise for cancer patients. shp2 phosphatase, also known as src homology 2 (sh2) domain containing tyrosine phosphatase 2 encoded by ptpn11, is a key mediator of the ras raf erk pathway.
Santosh Krishna Subramanian Phd On Linkedin Novel Small Molecule Here, we report a cellular thermal shift assay that reliably detects target engagement of shp2 inhibitors. using this assay, based on the discoverx incell pulse enzyme complementation technology, we characterized the binding of several shp2 allosteric inhibitors in intact cells. moreover, we demonstrate the robustness and reliability of a 384. Two types of small molecule inhibitors of shp2 have recently emerged. shp099 is an allosteric inhibitor of shp2, and we have recently developed 11a 1, as an active site inhibitor of shp2 [ 26 , 27. To identify novel shp2 inhibitor scaffolds, we screened an in house small molecule library collection against one of the most frequent shp2 oncogenic variants, e76k, using a protein thermal shift (pts) assay (to be published elsewhere). confirmed pts hits were then subjected to in vitro phosphatase inhibition assays using shp2 e76k. Here, we report the development of a cellular target engagement assay for shp2 wild type and mutant proteins utilizing the incell pulse assay platform. this assay is based on the cellular thermal.
Figure 5 From Novel Small Molecule Inhibitor For The Oncogenic Tyrosine To identify novel shp2 inhibitor scaffolds, we screened an in house small molecule library collection against one of the most frequent shp2 oncogenic variants, e76k, using a protein thermal shift (pts) assay (to be published elsewhere). confirmed pts hits were then subjected to in vitro phosphatase inhibition assays using shp2 e76k. Here, we report the development of a cellular target engagement assay for shp2 wild type and mutant proteins utilizing the incell pulse assay platform. this assay is based on the cellular thermal. To develop a cellular target engagement assay for shp2, we selected a set of known shp2 allosteric inhibitors and charac terized them first in vitro in biochemical inhibition and pts assays (table 1). we selected the novartis compound shp099 (30) as the prototypical example of a new class of shp2 allos teric inhibitors. Finally, we provide an example of the assay's ability to assess and prioritize novel shp2 inhibitors from our laboratory. given the relatively simple assay protocol and instrumentation, we propose that this cellular target engagement assay can be valuable for small molecule inhibitor screening campaigns against shp2 and other phosphatases.
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