PinA1 hydrochloride is a potent, preferential molecular glue degrader targeting CK1⍺ with DC50 of 46.9 nM in Jurkat cells (16 h), degrades CK1α via CRBN-dependent ubiquitination.
PinA1 induces CRBN-CK1α ternary complex formation with EC50 of 2.09 uM.
PinA1 shows negligible degradation forIKZF1 (Ikaros) levels, as well as GSPT1, SALL4, and other CK1 isoforms.
PinA1 promotes the recruitment of CRBN-CRL complexes, resulting in CK1α polyubiquitination and subsequent targeting to the 26S proteasome for degradation.
PinA1 activates the p53 signaling pathway in TP53-wild-type AML cells, upregulates p53 target genes, including CDKN1A(p21), MDM2, and GDF15, while has no such effect in TP53-mutant Kasumi-1 cells harboring biallelic TP53 loss-of-function mutations.
PinA1 markedly reduces the viability of TP53–wild-type AML cells harboring FLT3-ITD mutations (MOLM-13, MV4-11, and MOLM-14) with IC50 of <0.5 uM, but not TP53-mutant cell lines lacking FLT3-ITD mutations (Kasumi-1, KG-1, and THP-1).
PinA1 preferentially induces p53-associated transcriptomic reprogramming in TP53-wild-type AML cells, induces p53-mediated apoptosis both in AML cell lines and primary AML cells with minimal impact on normal hematopoietic cells.
PinA1 enhances anti-leukemia effects in combination with FLT3, BCL-2, or MDM2 inhibitors in FLT3-ITD-mutated AML cells in vitro and ex vivo.
PinA1 (36 mg/kg QD or 18 mg/kg BID) exhibits potent anti-leukemia effects in FLT3 ITD–positive AML xenograft mode.
PinA1 enhances anti-leukemia effects in combination with FLT3, BCL-2, or MDM2 inhibitors in FLT3-ITD-mutated AML cell line xenografts.