The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.

19 Aug 2024·ChemBioChem

IKZF2 Degradation: It′s Time to Take into Account it When Designing Cereblon‐Based PROTACs

Review

Author: Li, Minglei

AbstractProteolysis‐targeting chimera (PROTAC) has become a very important means of protein degradation and a new way of disease treatment. In particular, PROTACs constructed with ligands for E3 ligase cereblon account for more than 90 % of the PROTACs currently in clinical research. Notably, CRBN ligands themselves are a class of molecular glue compounds capable of degrading neo‐substrate proteins. Compared to the target proteins degradation, the degradation of neo‐substrates, especially IKZF2, has not received enough attention. Therefore, this review summarizes the currently published IKZF2 degraders derived from articles and patents, which are conducive to the design of PROTACs with desired IKZF2 degradation from the perspective of medicinal chemistry.

28 Dec 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Design and Development of IKZF2 and CK1α Dual Degraders

Q1 · MEDICINE

Article

Author: Kharas, Michael G ; Park, Sun-Mi ; Stavropoulos, Alexios ; Miyamoto, David K ; Curnutt, Nicole M ; Woo, Christina M

Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer.

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