Ufhyperloop Blog Targeting the RET Proteo-Oncogene

Targeting the RET Proteo-Oncogene

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The ret bv encodes a receptor tyrosine kinase (TK) expressed in progenitor cells during embryonic development and required for maturation of several cell lineages including peripheral nervous system formation, kidney morphogenesis and spermatogenesis. During this process RET binds to the GDNF family of ligands in association with one of four glycosylphosphatidylinositol (GPI) anchored cellular POM chains, triggering dimerization and autophosphorylation of specific tyrosine residues within its C terminus that then triggers downstream signalling cascades. These play a critical role in mediating cell survival, proliferation, differentiation and migration.

Germline activating mutations in RET are found to cause MEN2 and somatic activating mutations are found to drive the growth of medullary thyroid cancer (MTC). The first demonstration that therapeutically targeting RET could be effective was the discovery that ribozyme-mediated cleavage of mutant RET mRNA inhibited MTC cell growth in vitro and in xenograft models.

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We have previously shown that a number of anilinoquinazoline compounds have potent RET inhibitory activity and are selective against M918T RET. However, these compounds exhibit slow binding to RET as measured by the standard RET kinase assay protocol with varying time of compound pre-incubation with RET prior to addition of ATP. This phenomenon can lead to an underestimation of biochemical potency and mislead SAR analysis. In order to determine the effects of binding kinetics on selectivity we have assayed several compounds using the standard RET kinase IC 50 protocol, with and without varying levels of pre-incubation of RET with each compound for periods ranging from 0 minutes to 60 minutes prior to the addition of ATP.

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