Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia
Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M. Linhares, Dong Chen, Gloria Jih, Eric Perkey, Huang Huang, Miao He, Bo Wen, Yi Wang, Ke Yu, Stanley Chun-Wei Lee, Gwenn Danet-Desnoyers, Winifred Trotman, Malathi Kandarpa, Anitria Cotton, Omar Abdel-Wahab, Hongwei Lei, Yali Dou, Monica Guzman, Luke Peterson, Tanja Gruber, Sarah Choi, Duxin Sun, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka
Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M. Linhares, Dong Chen, Gloria Jih, Eric Perkey, Huang Huang, Miao He, Bo Wen, Yi Wang, Ke Yu, Stanley Chun-Wei Lee, Gwenn Danet-Desnoyers, Winifred Trotman, Malathi Kandarpa, Anitria Cotton, Omar Abdel-Wahab, Hongwei Lei, Yali Dou, Monica Guzman, Luke Peterson, Tanja Gruber, Sarah Choi, Duxin Sun, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka
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Research Article Hematology

Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia

Abstract

The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

Authors

Szymon Klossowski, Hongzhi Miao, Katarzyna Kempinska, Tao Wu, Trupta Purohit, EunGi Kim, Brian M. Linhares, Dong Chen, Gloria Jih, Eric Perkey, Huang Huang, Miao He, Bo Wen, Yi Wang, Ke Yu, Stanley Chun-Wei Lee, Gwenn Danet-Desnoyers, Winifred Trotman, Malathi Kandarpa, Anitria Cotton, Omar Abdel-Wahab, Hongwei Lei, Yali Dou, Monica Guzman, Luke Peterson, Tanja Gruber, Sarah Choi, Duxin Sun, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka

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Figure 1

Structure and in vitro activity of menin-MLL1 inhibitor MI-3454.

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Structure and in vitro activity of menin-MLL1 inhibitor MI-3454. (A) Che...
(A) Chemical structure of MI-3454. (B) Titration curve from fluorescence polarization competition assay for inhibition of the menin-MLL14–43 interaction by MI-3454. Mean ± SD, n = 3. mP, millipolarization. (C) Crystal structure of the menin–MI-3454 complex (1.24 Å). Menin is shown in surface representation (carbon atoms in gray, oxygen in red, nitrogen in dark blue, sulfur in yellow) and MI-3454 is shown in stick representation (carbon atoms in green; color coding for oxygen, nitrogen, and sulfur atoms is the same as for menin residues; fluorine atoms are in light blue). (D) Details of interactions of MI-3454 with menin. Color coding as in C. (E) Pharmacokinetic studies in mice performed for MI-3454 (mean ± SD, n = 3) demonstrating blood concentration of MI-3454 after oral (p.o.) dose of 100 mg/kg and intravenous (i.v.) administration at 15 mg/kg. (F) Titration curves from MTT cell viability assay performed after 7 days of treatment of human MLL leukemic cell lines (MLL-tr) with MI-3454: MV-4-11 (MLL-AF4), MOLM-13 (MLL-AF9), KOPN-8 (MLL-ENL), SEM (MLL-AF4), RS4-11 (MLL-AF4), and control leukemic cell lines (non–MLL-tr): K562, SET2, REH, and U937; mean ± SD, n = 4. Two to 3 independent MTT experiments were performed for each cell line. Representative graphs are shown. GI50 values correspond to MI-3454 concentrations needed for 50% inhibition of cell proliferation. (G) Quantitative RT-PCR performed in MV-4-11 cells (left) or MOLM13 cells (right) after 6 days of treatment with 50 nM MI-3454. Gene expression was normalized to HPRT1 and referenced to the DMSO-treated cells. Data represent 2 independent experiments, each performed in duplicate (mean ± SD, n = 4). P < 0.0001 for all genes tested calculated using Student’s 2-tailed t test. (H) Wright-Giemsa–stained cytospins for MV-4-11 and MOLM13 after 6 days of treatment with 50 nM MI-3454.