Identification of RET PROTAC with excellent degradation efficiency against medullary thyroid carcinoma

Abstract

Mutations and rearrangements of Rearranged during Transfection kinase (RET) are highly implicated with thyroid cancer. This study aimed to explore the therapeutic potential of a targeted protein degradation (TPD) strategy against RET-associated medullary thyroid carcinoma (MTC). The investigation of the structure-activity relationship (SAR) led to the identification of a novel RET-CRBN degrader, JW15 which possesses excellent degradation capability (DC50 = 0.3 nM) and potent anti-proliferative activity (GI50 =1.2 nM) on TT cells (MTC). Mechanistic studies revealed that JW15 degrades RET kinase via the ubiquitin-proteasome system (UPS) and effectively recruits cereblon (CRBN) E3 ligase in target engagement assays. Notably, JW15 exhibited superior suppression of RET phosphorylation and downstream signaling compared with selpercatinib. In addition, JW15 demonstrated greater efficacy than selpercatinib in inducing apoptosis and suppressing colony-forming capacity on TT cells, particularly at a concentration of 1 nM. JW15 administered intravenously at 20 mg/kg twice weekly demonstrated significant antitumor efficacy, showing 70% tumor growth inhibition in RET Ba/F3 xenograft models over 13 days. Taken together, our study provides fundamental guidelines for structure-guided design and optimization for the development of RET degraders, offering a promising strategy for targeting RET-driven cancers.