Rearranged during transfection (RET) is a transmembrane receptor within the tyrosine kinase family. RET aids in embryonic development and is required for the maintenance of some adult tissues. In healthy cells, the extracellular portion of RET binds to its native substrates, which activates the Ras-MAPK signaling pathway. In aberrant cells, point mutations or chromosomal rearrangements generate constitutively active RET, which drives numerous human cancers.

Inhibitors have been deployed as therapeutics targeting RET-driven cancers with varying levels of success. Multi-targeted tyrosine kinase inhibitors suffer from dose-limiting toxicity, and while RET-selective inhibitors have expanded the therapeutic window and improved clinical outcomes, resistance mutations have begun to emerge in the context of RET inhibition therapy, highlighting a rising clinical need.

Targeted Protein Degradation (TPD) has unique characteristics giving degraders the potential to maintain robust pharmacology in the face of resistance. First, a degrader’s binding to the kinase may be energetically dominated by cooperativity between the kinase and the E3 ligase during ubiquitination. Therefore, a residue change in the kinase domain may present a smaller challenge to the overall binding event than it would for an inhibitor. Second, degraders act catalytically, and rapid degradation kinetics could compensate for a loss in binding affinity to the target protein. Therefore, degraders may prove more resilient to resistance-causing secondary mutations in RET than are RET inhibitors.

Here we describe the medicinal chemistry efforts that led to CFT27796, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader. In vitro, CFT27796 promotes potent degradation of the wild-type and mutant RET kinase domains. In vivo, oral dosing of CFT27796 in xenograft models of RET-driven cancers leads to robust tumor regression.

Richard Deibler

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