Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their ...Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.展开更多
To the Editor:Cereblon(CRBN)has emerged as a promising therapeutic target,enabling the design of proteolysis-targeting chimeras(PROTACs)and molecular glues(MGs)for targeted protein degradation1.The immunomodulatory im...To the Editor:Cereblon(CRBN)has emerged as a promising therapeutic target,enabling the design of proteolysis-targeting chimeras(PROTACs)and molecular glues(MGs)for targeted protein degradation1.The immunomodulatory imide drugs(IMiDs),such as thalidomide,lenalidomide and pomalidomide,represent classical CRBN ligands and have been widely used in the treatment of hematopoietic malignancies.These IMiDs exert their immunomodulatory and anti-inflammatory effects by binding to CRBN and triggering the degradation of neosubstrates,including IKZF1 and IKZF3,which are crucial for B and T cells biology2.展开更多
基金supported by the National Natural Science Foundation of China(No.82404417)Key Project of North China University of Science and Technology(ZD-YG-202408)State Key Laboratory of National Security Specially Needed Medicines Program(No.LTMC2022ZZ006).
文摘Objectives:Immunomodulatory drugs(IMiDs),functioning as molecular glue degraders,have been approved for treating various hematological malignancies;however,the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment.The study aimed to develop degraders with potent efficiency and low toxicity.Methods:Phenotypic profiling,elaborate structure-activity relationships(SAR),rational drug design and degradation profiles investigations,quantitative proteomics analysis and cell-based functional studies,and pharmacokinetic studies were conducted to develop more potent degraders.Results:This study developed novel CRBN-binding moieties throughmethylene deletion in lenalidomide’s isoindole core.Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs.IMiDs,with submicromolar potency.MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3(IKZF1/3)with nanomolar potency via a CRBN-dependent pathway.Mechanistically,MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGDC9 exhibited favorable pharmacokinetic properties in vivo.Furthermore,MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells.Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.
基金supported by the National Natural Science Foundation of China(22037002,32121005)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212702,China)+1 种基金National Special Fund for State Key Laboratory of Bioreactor Engineering(2060204,China)Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(2021 Sci&Tech 03-28,China).
文摘To the Editor:Cereblon(CRBN)has emerged as a promising therapeutic target,enabling the design of proteolysis-targeting chimeras(PROTACs)and molecular glues(MGs)for targeted protein degradation1.The immunomodulatory imide drugs(IMiDs),such as thalidomide,lenalidomide and pomalidomide,represent classical CRBN ligands and have been widely used in the treatment of hematopoietic malignancies.These IMiDs exert their immunomodulatory and anti-inflammatory effects by binding to CRBN and triggering the degradation of neosubstrates,including IKZF1 and IKZF3,which are crucial for B and T cells biology2.
