SJ11646 is a potent, dasatinib-based, cereblon-mediated LCK PROTAC degrader with DC50 of 0.00838 pM in in KOPT-K1 T-ALL cells, cytotoxic IC50 of 0.083pM.
SJ11646 induces a loss of LCK phosphorylation (pLCK) in KOPT-K1 T-ALL cells.
SJ11646 (100nM) induces a 92.6% LCK degradation and complete loss of pLCK within 3 hours.
SJ11646 shows superior cytotoxicity relative to dasatinib against a panel of T-ALL blasts collected from 10 patient-derived xenografts (PDX).
SJ11646 shows lower toxicity than dasatinib in both CD34+ cells (LC50 of 726.42 and 92.88nM, respectively), with similar results in peripheral blood mononuclear cells (LC50 of 13.84 and 2.81nM for, respectively).
SJ11646 is a potent and selective degrader of ABL and SRC family kinases, retaines dasatinib's targeting selectivity without inducing new interactions with other kinases.
SJ11646 exhibits cytotoxicity with an estimated LC50 of 0.0123 pM in B-ALL cell line SUP-B15 which harbors the BCR-ABL fusion gene.
SJ11646 induces prolonged suppression of LCK signaling in vitro and in vivo, has superior in vivo anti-leukemic efficacy compared to dasatinib.