UM171 is a small molecule first discovered in Canada and published in 2014, known for its ability to enhance hematopoietic stem cell renewal (Fares I. et al. Science 2014, 345, 1509–1512). UM171 activates the CULLIN3KBTBD4 ubiquitin ligase, which specifically targets the LSD1-CoREST repressor complex for proteasomal degradation (Chagraoui J. et al. Cell Stem Cell. 2021, 28, 48–62). A phase 1-2 trial of UM171-expanded cord blood (CB) transplants demonstrated safety and favorable preliminary efficacy (Cohen S. et al. Blood Adv. 2023, 7, 5717-5726).
UM171 is highly hydrophobic. For example, when a trastuzumab biosimilar was conjugated to UM171 using an ethylene linker, over 38% aggregation was observed for an ADC with a DAR of 5 via surface amine labeling. The majority of the ADC precipitated, with only 18% recovery (data from DCM11433). This makes UM171 a perfect candidate for using a superhydrophilic AqT linker to improve solubility and conjugation performance.
The AqT®-UM171 (CM81310) drug asset is currently available for partner evaluation. This drug asset enables efficient loading of four to six drug molecules per antibody without significant precipitation.