2. Academic Validation
  3. Preclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) in KMT2A- and NPM1-altered leukemias

Preclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) in KMT2A- and NPM1-altered leukemias

  • Blood. 2024 Sep 12;144(11):1206-1220. doi: 10.1182/blood.2023022480.
Min Chul Kwon 1,  Jan Willem Thuring 2,  Olivier Querolle 2,  Xuedong Dai 3,  Tinne Verhulst 1,  Vineet Pande 2,  Ann Marien 1,  Dries Goffin 1,  Daniela V Wenge 4 5,  Hong Yue 6 7,  Jevon A Cutler 4 5,  Cyrus Jin 6 7,  Florian Perner 4 5,  Shanna M Hogeling 8,  Paul L Shaffer 9,  Frank Jacobs 2,  Petra Vinken 2,  Wei Cai 3,  Vikki Keersmaekers 1,  Filmon Eyassu 1,  Balpreet Bhogal 9,  Karin Verstraeten 1,  Sara El Ashkar 1,  Jennifer A Perry 4 5,  Prathiba Jayaguru 10,  Laura Barreyro 10,  Anna Kuchnio 1,  Nicolas Darville 2,  Daniel Krosky 9,  Gregor Urbanietz 2,  Bie Verbist 11,  James P Edwards 9,  Glenn S Cowley 9,  Robert Kirkpatrick 9,  Ruth Steele 9,  Lucille Ferrante 12,  Christina Guttke 10,  Nikki Daskalakis 12,  E Christine Pietsch 13,  David M Wilson 2,  Ricardo Attar 10,  Yusri Elsayed 13,  Eric S Fischer 6 7,  Jan Jacob Schuringa 8,  Scott A Armstrong 4 5,  Kathryn Packman 14,  Ulrike Philippar 1
Affiliations

Affiliations

  • 1 Discovery Oncology, Janssen R&D, Beerse, Belgium.
  • 2 Discovery Product Development and Supply, Janssen R&D, Beerse, Belgium.
  • 3 Discovery Product Development and Supply, Janssen R&D, Shanghai, China.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • 5 Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • 7 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • 8 Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 9 Discovery Product Development and Supply, Janssen R&D, Spring House, PA.
  • 10 Translational Research, Janssen R&D, Spring House, PA.
  • 11 TMEDS, Janssen R&D, Beerse, Belgium.
  • 12 Early Development, Janssen R&D, Spring House, PA.
  • 13 Discovery Oncology, Janssen R&D, Spring House, PA.
  • 14 Early Development, Janssen R&D, Cambridge, MA.
PMID: 38905635 DOI: 10.1182/blood.2023022480
Abstract

The interaction between menin and histone-lysine N-methyltransferase 2A (KMT2A) is a critical dependency for KMT2A- or nucleophosmin 1 (NPM1)-altered leukemias and an emerging opportunity for therapeutic development. JNJ-75276617 (bleximenib) is a novel, orally bioavailable, potent, and selective protein-protein interaction inhibitor of the binding between menin and KMT2A. In KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) acute myeloid leukemia (AML) cells, JNJ-75276617 inhibited the association of the menin-KMT2A complex with chromatin at target gene promoters, resulting in reduced expression of several menin-KMT2A target genes, including MEIS1 and FLT3. JNJ-75276617 displayed potent antiproliferative activity across several AML and acute lymphoblastic leukemia (ALL) cell lines and patient samples harboring KMT2A or NPM1 alterations in vitro. In xenograft models of AML and ALL, JNJ-75276617 reduced leukemic burden and provided a significant dose-dependent survival benefit accompanied by expression changes of menin-KMT2A target genes. JNJ-75276617 demonstrated synergistic effects with gilteritinib in vitro in AML cells harboring KMT2A-r. JNJ-75276617 further exhibited synergistic effects with venetoclax and azacitidine in AML cells bearing KMT2A-r in vitro, and significantly increased survival in mice. Interestingly, JNJ-75276617 showed potent antiproliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A cocrystal structure of menin in complex with JNJ-75276617 indicates a unique binding mode distinct from Other menin-KMT2A inhibitors, including revumenib. JNJ-75276617 is being clinically investigated for acute leukemias harboring KMT2A or NPM1 alterations, as a monotherapy for relapsed/refractory acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

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