Ikaros family zinc finger protein 1, Ikaros family zinc finger protein 3, and Casein kinase 1 alpha as Cereblon neosubstrates (IKZF1/IKZF3/CK1α CRBN neosubstrates)

IKZF1 (Ikaros), IKZF3 (Aiolos), and Casein kinase 1 alpha (CK1α) are specific proteins targeted for degradation by the CRL4-CRBN E3 ubiquitin ligase complex in the presence of immunomodulatory drugs (IMiDs) (UniProt Q13422, Q9UKL7, P48729) [1, 2, 3]. These proteins are termed neosubstrates because their recruitment to Cereblon (CRBN) is dependent on the binding of a small-molecule molecular glue such as lenalidomide or pomalidomide (UniProt Q96SW2) [4, 5, 6]. IKZF1 and IKZF3 are zinc-finger transcription factors essential for the development and survival of B-lymphocytes; their degradation leads to the down-regulation of IRF4 and MYC, resulting in the inhibition of multiple myeloma cell growth [5, 8]. CK1α is a serine/threonine kinase that regulates the cell cycle and p53 activity; its degradation is the primary mechanism by which lenalidomide treats myelodysplastic syndrome with 5q deletion [6, 9]. This targeted protein degradation approach allows for the depletion of previously undruggable transcription factors and kinases with high specificity [10]. The clinical success of targeting these neosubstrates has established a paradigm for the development of novel Cereblon E3 ligase modulators (CELMoDs) for various hematologic and autoimmune diseases [11].

Other names

IkarosAiolosCK1αCSNK1A1IKZF1IKZF3IMiD targetsCereblon neosubstrates

Molecular glue-induced targeted protein degradation via the CRL4-CRBN E3 ubiquitin ligase complex