| Author |
Tae‐Jun Kim, Seongu Seong, Jung‐Ae Kim, Taeyeon Kwon, Hyun Jin Kim, Jeong‐Hoon Kim, Jong Yeon Hwang, Jin Hwa Cho, Kyoungmin Choi
|
| Abstract |
Widely interspaced zinc finger motifs (WIZ) is a therapeutic target for the treatment of sickle cell disease through the induction of fetal hemoglobin. Here, we report the identification and optimization of novel cereblon (CRBN)‐based molecular glue degraders targeting the WIZ transcription factor. Using CRISPR‐engineered WIZ‐HiBiT reporter cells, we performed high‐throughput screening of a CRBN‐focused chemical library and identified a hit compound,
6a
, which contains an
N
‐isoxazol‐3‐yl amide group on a benzoisoindolinone scaffold. Subsequent structure–activity relationship studies focused on a five‐membered heteroaryl substituent of amide led to the development of compound
9l
(DC
50
= 8.7 nM, D
max
= 81.7%), which exhibited potent WIZ degradation. Mechanistic studies demonstrated that
9l
induces rapid and sustained WIZ depletion through CRBN‐dependent proteasomal degradation, by facilitating the formation of a ternary complex between WIZ and CRBN. Importantly,
9l
‐mediated WIZ depletion in HUDEP‐2 cells resulted in γ‐globin induction, confirming the functional outcome of targeted WIZ degradation. Collectively, these results define a structurally distinct chemotype of CRBN‐based WIZ degraders, providing a novel scaffold for the pharmacological induction of γ‐globin expression.
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