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.

01 Apr 2023·Cancer Cell

Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Article

Author: Schurer, Alexandra ; Chang, Kathryn ; Kharas, Michael G ; Park, Sun-Mi ; Curnutt, Nicole M ; Miyamoto, David K ; Xu, Wenqing ; Woo, Christina M ; Han, Grace Y Q ; Tran, Nathan L ; Kim, Jun Hyun ; Velleca, Anthony ; Chan, Mandy

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

Accounts of Chemical Research

Probing the E3 Ligase Adapter Cereblon with Chemical Biology

Article

Author: Woo, Christina M. ; Xu, Wenqing

ConspectusThe E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological development and subsequently identified as the target of thalidomide and lenalidomide, therapeutic agents used in the treatment of hematopoietic malignancies. Both thalidomide and lenalidomide have been repurposed as ligands for targeted protein degradation therapeutic modalities. These agents were proposed to mimic a naturally occurring ligand, although the native substrate recognition mechanism of CRBN remained elusive. Chemical biology, which involves the use of chemical tools to modulate and probe biological systems, can provide unique insights into the molecular mechanisms and interactions of proteins with their cognate ligands. Here we describe our use of chemical biology approaches, including photoaffinity labeling, chemical proteomics, and targeted protein degradation, to interrogate the biological activities of CRBN in the presence or absence of its ligands. Our development of a photoaffinity labeling probe derived from lenalidomide, termed photolenalidomide, enabled mapping of the binding site on CRBN and identification of a new target recruited to CRBN by lenalidomide through chemical proteomics. Further derivatization of the lenalidomide scaffold afforded DEG-77, a potent degrader with therapeutic efficacy against acute myeloid leukemia. Our parallel development of chemically defined probes that are inspired by heterobifunctional targeted protein degradation agents and functionally engage CRBN in cells revealed that thalidomide is a peptidomimetic of an underappreciated protein modification termed the C-terminal cyclic imide, which arises from intramolecular cyclization of asparagine or glutamine residues and represents a degron endogenously recognized by CRBN. Protein engineering and proteomic efforts validated the CRBN-dependent regulation of proteins bearing the C-terminal cyclic imide modification in vitro and in cells and the prevalence of the C-terminal cyclic imide in the biological system. Application of C-terminal cyclic imides as a class of cyclimid ligands for targeted protein degradation led to the development of a variety of heterobifunctional degraders with distinct efficacy and target selectivity, whereas examination of the occurrence of C-terminal cyclic imides as a form of protein damage uncovered the intrinsic and extrinsic factors that predispose peptides and proteins to C-terminal cyclic imide formation and the role of CRBN in mitigating the accumulation of damaged proteins with a propensity for aggregation. Future investigation of C-terminal cyclic imides, synthetic ligands, and their relationship to CRBN biology will illuminate regulatory mechanisms that are controlled by CRBN and drive the pursuit of additional functional chemistries on proteins and the biological pathways that intercept them.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse Large B-Cell Lymphoma	Preclinical	United States	Harvard University	12 Dec 2023
Ovarian Cancer	Preclinical	United States	Harvard University	12 Dec 2023
Acute Myeloid Leukemia	Preclinical	United States	Memorial Sloan Kettering Cancer Center	10 Apr 2023

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