Toxicological Sciences: Developmental Toxicology Profile of the IRAK4 Degrader KT-474
Toxicological Sciences: Developmental Toxicology Profile of the IRAK4 Degrader KT-474
Bradley E Enerson, Gregg Cappon, Yatao Shi, Dirk M Walther, Veronica Campbell, Dapeng Chen, Eric Kuhn, Ginny Massa, Chris Ho, Xiaozhang Zheng, Jing Yuan, Kirti Sharma, Andreas M Holhbaum, Anthony Slavin, Nan Ji, Nello Mainolfi, Matthew M Weiss
KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed to be devoid of immunomodulatory imide drug (IMiD)-related neosubstrate degradation. Like KT-474, most degraders in clinical trials to date rely on CRBN for E3 ligase recruitment to harness the ubiquitin-proteasome system to selectively degrade disease-associated proteins. Structural similarities of the CRBN-binding portion of these degraders to IMiDs (e.g., thalidomide) have raised safety concerns due to potential degradation of CRBN neosubstrates implicated in teratogenicity, such as SALL4. To address this theoretical concern, the potential of KT-474 to degrade CRBN neosubstrates in vitro and cause developmental toxicity in vivo was evaluated. Proteomic analyses across three human cell systems (peripheral blood mononuclear cells [PBMCs], induced pluripotent stem cells, and SK-N-DZ cells) demonstrated that KT-474 selectively degraded IRAK4 without affecting SALL4, or other detected CRBN neosubstrates. In embryo-fetal development studies, no KT-474–related malformations or embryo-fetal toxicity was observed in rats or rabbits at the highest doses tested. Associated exposures (AUC) provided 23- to 9-fold multiples, respectively, over exposures at the clinical dose of KT-474 associated with robust degradation of IRAK4 and early signals of efficacy. Deep IRAK4 degradation by KT-474 in primary rat cells, rabbit PBMCs, and a range of tissues provides confidence in the appropriateness of the animal species tested. Taken together, these data clearly differentiate KT-474 from IMiDs, support that CRBN-mediated teratogenicity seen with IMiD drugs is neosubstrate-driven, and demonstrate that structure-based design can generate highly selective degraders devoid of teratogenic risk.
