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Ref Type Journal Article
PMID (25817203)
Authors Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T, Wang J, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL, Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J
Title Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
Journal Cancer cell
Vol 27
Issue 4
Date 2015 Apr 13
URL
Abstract Text Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MI-503 MI-503 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MI-503 MI 503|MI 503 MI-503 inhibits the interaction between Menin and MLL (KMT2A), potentially leads to inhibition of growth and migration of tumor cells (PMID: 25817203, PMID: 29142068).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A - MLLT3 acute myeloid leukemia sensitive MI-503 Preclinical - Patient cell culture Actionable In a preclinical study, MI-503 inhibited growth of an acute myeloid leukemia (AML) cell line and primary AML samples harboring KMT2A-MLLT3 (MLL-AF9) in culture (PMID: 25817203). 25817203
KMT2A - EP300 acute myeloid leukemia sensitive MI-503 Preclinical - Patient cell culture Actionable In a preclinical study, MI-503 inhibited growth of a primary acute myeloid sample harboring KMT2A-EP300 in culture (PMID: 25817203). 25817203
KMT2A - AFF1 acute myeloid leukemia sensitive MI-503 Preclinical - Cell line xenograft Actionable In a preclinical study, MI-503 reduced expression of KMT2A (MLL) fusion target genes, inhibited growth of an acute myeloid leukemia (AML) cell lines harboring KMT2A-AFF1 (MLL-AF4) in culture, and inhibited tumor growth and progression in an AML cell line xenograft model harboring KMT2A-AFF1 (MLL-AF4) (PMID: 25817203). 25817203
KMT2A - MLLT1 acute myeloid leukemia sensitive MI-503 Preclinical - Cell culture Actionable In a preclinical study, MI-503 inhibited growth of an acute myeloid leukemia cell line harboring KMT2A-MLLT1 (MLL-ENL) in culture (PMID: 25817203). 25817203
KMT2A - MLLT3 leukemia sensitive MI-503 Preclinical Actionable In a preclinical study, MI-503 reduced progression and improved survival of a mouse leukemia model expressing KMT2A-MLLT3 (MLL-AF9) (PMID: 25817203). 25817203
KMT2A fusion acute myeloid leukemia predicted - sensitive MI-503 Preclinical - Cell culture Actionable In a preclinical study, MI-503 inhibited growth of several acute myeloid leukemia (AML) cell lines and primary AML samples harboring KMT2A (MLL) fusions in culture (PMID: 25817203). 25817203