AH078 is a PROTAC -based CK1δ/ε degrader ( DC50 =0.55 μM, D max =70%) that lacks subtype selectivity between CK1δ and CK1ε. AH078 induces target protein degradation either by recruiting the CUL4-CRBN E3 ligase complex and proteasome, or via the VHL - and ubiquitin-dependent pathway. AH078 also exhibits selectivity for CK1α, and is widely applicable to research related to colon cancer, pancreatic cancer, breast cancer, ovarian cancer, chronic lymphocytic leukemia, acute myeloid leukemia, glioma, and metastatic breast adenocarcinoma [1] [2] [3]. (Pink: CK1δ and CK1ε ligand; Blue: VHL ligand; Black: linker ).
In Vitro, AH078 potently binds to CK1δ in permeabilized cells, with an EC50 of 3.2 nM[3]. AH078 degrades CK1δ in MV4-11 HiBiT-CK1δ cells, with a DC50 of 0.55 μM and a Dmax of 70.1% after 6 h of incubation[3]. AH078 (3-10 μM; 9 h) induces a dose-dependent slowdown of cell cycle progression in MEC-1 WT cells. At the concentration of 10 μM, it reduces the accumulation of cells at the G2/M phase boundary and increases the proportion of S-phase cells[2]. AH078 (3-10 μM; 9 h) induces a dose-dependent slowdown of cell cycle progression in HG-3 WT cells, reduces cell accumulation at the G2/M phase boundary, and increases the proportion of S-phase cells at a concentration of 10 μM[2]. AH078 (3-10 μM; 6 d) significantly inhibits microenvironment-induced proliferation of primary human chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner, with the strongest effect observed under the incubation condition of 10 μM for 6 days[2]. AH078 (0.01-30 μM; 6 h) potently degrades endogenous CK1δ (DC50=200 nM) and CK1ε in HEK293 cells after a 6 h incubation, while only exerting weak degradation effects on CK1α at concentrations ≥10 μM[3]. AH078 (0.03-1.19 μM; 6 h)-mediated degradation of CK1δ depends on functional Cullin ring ligases, which is confirmed by experimental results showing that the degradation is reversed upon treatment with the neddylation inhibitor MLN4924[3].
References:
[1]. Arnold M, et al. Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs). Molecules. 2025;30(22):4452. Published 2025 Nov 18.
[2]. Mikulova A, et al. Casein kinase 1δ/ε inhibition suppresses CLL proliferation through cell‐intrinsic and microenvironmental mechanisms[J]. HemaSphere, 2026, 10(3): e70343.
[3]. Haag A, et al. Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε. J Med Chem. 2025;68(1):506-530.
In Vitro, AH078 potently binds to CK1δ in permeabilized cells, with an EC50 of 3.2 nM[3]. AH078 degrades CK1δ in MV4-11 HiBiT-CK1δ cells, with a DC50 of 0.55 μM and a Dmax of 70.1% after 6 h of incubation[3]. AH078 (3-10 μM; 9 h) induces a dose-dependent slowdown of cell cycle progression in MEC-1 WT cells. At the concentration of 10 μM, it reduces the accumulation of cells at the G2/M phase boundary and increases the proportion of S-phase cells[2]. AH078 (3-10 μM; 9 h) induces a dose-dependent slowdown of cell cycle progression in HG-3 WT cells, reduces cell accumulation at the G2/M phase boundary, and increases the proportion of S-phase cells at a concentration of 10 μM[2]. AH078 (3-10 μM; 6 d) significantly inhibits microenvironment-induced proliferation of primary human chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner, with the strongest effect observed under the incubation condition of 10 μM for 6 days[2]. AH078 (0.01-30 μM; 6 h) potently degrades endogenous CK1δ (DC50=200 nM) and CK1ε in HEK293 cells after a 6 h incubation, while only exerting weak degradation effects on CK1α at concentrations ≥10 μM[3]. AH078 (0.03-1.19 μM; 6 h)-mediated degradation of CK1δ depends on functional Cullin ring ligases, which is confirmed by experimental results showing that the degradation is reversed upon treatment with the neddylation inhibitor MLN4924[3].
References:
[1]. Arnold M, et al. Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs). Molecules. 2025;30(22):4452. Published 2025 Nov 18.
[2]. Mikulova A, et al. Casein kinase 1δ/ε inhibition suppresses CLL proliferation through cell‐intrinsic and microenvironmental mechanisms[J]. HemaSphere, 2026, 10(3): e70343.
[3]. Haag A, et al. Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε. J Med Chem. 2025;68(1):506-530.