PXD041735 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia |
Description | Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, MLL1) rearranged (KMT2A-r) and nucleophosmin mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with Lenalidomide or Iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. Recently, the novel IKAROS degrader Mezigdomide was developed and has greatly enhanced IKAROS protein degradation. In this study we show that Mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to Lenalidomide and Iberdomide. Further, we demonstrate that Mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with Menin inhibitors. We show that the superior activity of Mezigdomide compared to Lenalidomide or Iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent Mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of Mezigdomide with a Menin inhibitor increased survival and prevented the development of recently described MEN1 mutations. These results support prioritization of Mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors. |
HostingRepository | PRIDE |
AnnounceDate | 2024-02-15 |
AnnouncementXML | Submission_2024-02-15_10:13:05.060.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Eric Fischer |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | iodoacetamide derivatized residue |
Instrument | timsTOF Pro 2 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-04-22 12:32:50 | ID requested | |
⏵ 1 | 2024-02-15 10:13:05 | announced | |
Publication List
Bourgeois W, Cutler JA, Aubrey BJ, Wenge DV, Perner F, Martucci C, Henrich JA, Klega K, Nowak RP, Donovan KA, Boileau M, Wen Y, Hatton C, Apazidis AA, Olsen SN, Kirmani N, Pikman Y, Pollard JA, Perry JA, Sperling AS, Ebert BL, McGeehan GM, Crompton BD, Fischer ES, Armstrong SA, Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML. Blood, 143(15):1513-1527(2024) [pubmed] |
10.1182/blood.2023021105; |
Keyword List
submitter keyword: MENIN-KMT2A, Menin inhibitor, acute myeloid leukemia,Mezigdomide, IKAROS |
Contact List
Eric Fischer |
contact affiliation | Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
contact email | eric_fischer@dfci.harvard.edu |
lab head | |
Eric Fischer |
contact affiliation | Dana-Farber Cancer Institute |
contact email | eric_fischer@dfci.harvard.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD041735
- Label: PRIDE project
- Name: Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia