This study describes the development of dKIF976, a novel cereblon (CRBN)-based degrader targeting the mitotic kinesin KIF11, a protein essential for cell division and a long-standing anticancer target. Traditional KIF11 inhibitors have shown limited clinical success due to toxicity, particularly myelosuppression. To address this, the authors designed a first-in-class degrader antibody conjugate (DAC) using dKIF976 as a payload.
In preclinical experiments, dKIF976 induced rapid, selective, and dose-dependent degradation of KIF11, leading to mitotic arrest and strong inhibition of cancer cell growth at sub-nanomolar potency. The effects were shown to depend on CRBN-mediated proteasomal degradation and were highly selective for KIF11. When incorporated into antibody conjugates, the degrader demonstrated antigen-dependent activity, with enhanced potency in cells expressing higher levels of the target antigen.
Overall, the study introduces a new therapeutic strategy that combines targeted protein degradation with antibody-based delivery, suggesting that degrader-based payloads may improve the therapeutic window of KIF11-targeted therapies and represent a broader platform for cancer treatment development.
Feng Y, Fan M, Slotnick N, Su J, Huang P, Liu J, et al. (June 2025). "A first-in-class KIF11 degrader antibody conjugate (DAC) as a potential therapy targeting a broad spectrum of cancers". Journal of Clinical Oncology. 43 (16_suppl): 3092. doi:10.1200/JCO.2025.43.16_suppl.3092. ISSN 0732-183X.