DMPK Optimization of Proteolysis-Targeting Chimeras

Twenty years have passed since the first PROTAC was reported, and many companies have brought protein degraders to preclinical and clinical development. This leads to the crucial question of whether new generations of targeted protein degraders are safe and effective. Shen points out that no major safety-related issues have been observed with PROTAC drugs in clinical programs. He does not anticipate any major safety issues with ATAC degraders, even though clinical data on PROTAC safety is still limited, especially with respect to long-term outcomes. Shen’s optimism is shared by Tozzo. “By leveraging ASGPR,” Tozzo says, “we are engaging the natural machinery that the body is already using for protein degradation.” Another key question involves whether the efficacy of various protein degraders may diminish over time. In the case of PROTACs, Shen notes that there is no evidence from clinical trials that they are more prone to resistance development than standard inhibitors. However, preclinical studies suggest that defects in the E3-ubiquitination system could become a source of resistance to PROTACs. As Shen explains, “Time will tell whether any of the resistance mechanisms observed in preclinical studies may emerge in the clinical setting.” Despite the many unknowns, the companies we interviewed were optimistic about the prospect of clinical trials for their targeted protein degraders. Nasveschuk notes that C4 Therapeutics has three projects that are in Phase I trials, and multiple other drugs in the preclinical stage. Hansen also emphasizes the success of Nurix’s therapies that degrade a protein called Bruton’s tyrosine kinase (BTK). She notes that the company’s lead BTK degrader, NX-2127, has already demonstrated proof of efficacy in ongoing Phase I trials: “Thus far, we have demonstrated rapid, robust, and sustained BTK degradation independent of BTK mutations.” Tozzo likewise suspects that ATAC inhibitors will perform well in clinical trials. She states, “Based on the robust degradation we have observed in our nonhuman primate studies with our proof-of-concept ATAC degraders, we anticipate good translation of ATAC degradation activity in the clinic.”