Design and Development of IKZF2 and CK1α Dual Degraders
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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
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Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in LymphomaPathologyCharacterizing the MSI2 network in leukemiaIdentification of therapeutic targets for leukemia stem cells in AML-iPSC modelsUncovering the role for MSI2 network in hematopoietic stem cellsThe role of the Musashi family in hematopoiesisHarvard University FundingUS Department of Defense FundingIdentification of therapeutic targets for leukemia stem cells in AML-iPSC modelsUncovering the role for MSI2 network in hematopoietic stem cellsUnderstanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in LymphomaCharacterizing the MSI2 network in leukemiaStarr Cancer Consortium FundingDana Farber and Harvard Cancer Center Funding