RESUMO
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.
Assuntos
Caseína Quinase Ialfa , Neoplasias Ovarianas , Humanos , Feminino , Linhagem Celular Tumoral , Lenalidomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Caseína Quinase Ialfa/metabolismo , Proteólise , Fator de Transcrição Ikaros/metabolismoRESUMO
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.
Assuntos
Caseína Quinase Ialfa , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Caseína Quinase Ialfa/genética , Caseína Quinase Ialfa/metabolismo , Hematopoese , Fator de Transcrição Ikaros/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Fatores de TranscriçãoRESUMO
We present here the complete genomes of two Streptomyces bacteriophages, Satis and JustBecause. Both phages were isolated directly from soil samples collected in St. Louis, MO, and present with an unusual prolate head morphology and large genome lengths of over 180 kb.
