Olverembatinib (HQP1351, GZD824) is an orally bioavailable multikinase inhibitor targeting a broad spectrum of mutant KIT kinases (KIT-V559D IC50=1.4 nM).
Olverembatinib (HQP1351, GZD824) also inhibits Bcr-Abl (WT) and Bcr-Abl (T315I) with IC50 of 0.34 nM and 0.68 nM, respectively.
Olverembatinib (HQP1351, GZD824) strongly inhibited wild-type KIT kinase and KIT kinases with primary mutations within exon 11 (L576P and V559D), with an inhibition rate of over 90% at 10 nM.
Olverembatinib (HQP1351, GZD824) showed strong inhibitory effect on KIT kinase with secondary mutations in the ATP-binding pocket (V559D/T670I and V559D/V654A).
The inhibition rates on KIT with A-loop mutations (A829P, D816H and D816 V) were relatively weaker at 10 nM (20–40%).
Olverembatinib (HQP1351, GZD824) exhibited potent binding affinities to additional kinases at 10 nM, including BRAF (V600E), DDR1, FLT3, PDGFRB, RET (M918T), TAK1 and TIE2.
Olverembatinib (HQP1351, GZD824) shows antiproliferative activity in GIST cells with KIT mutations (GIST T1 cells IC50=27 nM), inhibits colony formation, cell migration and invasion, induces cell cycle arrest and cell apoptosis, regulates KIT oncogenic signaling proteins in vitro.
Olverembatinib (HQP1351, GZD824) exhibits antitumor activity in GIST xenograft models in vivo. Olverembatinib (HQP1351) also is a potent Omicron NTD-mediated cytokine release inhibitor.