SIAIS056 is a BCR-ABL PROTAC degrader with a DC50 value of 0.18 nM. It inhibits the BCR-ABL signaling pathway in a time-dependent manner in K562 cells and reduces the phosphorylation levels of BCR-ABL and its downstream molecules, STAT5 and CRKL. SIAIS056 can induce the degradation of various clinically relevant BCR-ABL resistant mutants and exhibits antiproliferative activity against K562 and 32D-BCR-ABL cells. Additionally, it can cause significant tumor regression in K562 xenograft models and is applicable for leukemia research.

Bcr-Abl:0.18 μM (DC50)

SIAIS056 (2 days) reduces antiproliferative activity against K562 and 32D-BCR-ABL cells. At concentrations ranging from 0-100 μM for up to 24 hours, SIAIS056 inhibits the BCR-ABL signaling pathway in K562 cells in a time-dependent manner, leading to a decrease in phosphorylation of BCR-ABL and downstream molecules such as STAT5 and CRKL. Additionally, SIAIS056 (0-300 nM, 16 hours) demonstrates the ability to overcome tyrosine kinase inhibitor resistance caused by most clinically common mutations in BCR-ABL, as observed in the 32D mouse myeloid cell line, including both wild-type and cell lines with mutations such as G250E, E255V, V299L, F317L, F317V, T315A, and T315I.

SIAIS056 (1-10 mg/kg, intraperitoneal injection, once daily for 10 consecutive days) effectively degrades the BCR-ABL protein, demonstrating significant anti-leukemia activity in a mouse xenograft model of K562 cells.