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Janssen R&D

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Blood, Jun 21 2024, blood.2023022480 | https://doi.org/10.1182/blood.2023022480 Preclinical efficacy of potent and selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias

Min Chul Kwon ¹, Jan Willem Thuring ¹, Olivier Querolle ², Xuedong Dai ³, Tinne Verhulst¹, Vineet Pande ¹, Ann Marien ¹, Dries Goffin ¹, Daniela V Wenge ⁴, Hong Yue⁴, Jevon A Cutler ⁴, Cyrus Jin ⁴, Florian Perner⁵, Shanna M Hogeling ⁶, Paul L Shaffer⁷, Frank Jacobs¹, Petra Vinken ⁸, Wei Cai ⁹, Vikki Keersmaekers ¹⁰, Filmon Eyassu¹, Balpreet Bhogal⁹, Karin Verstraeten ¹, Sara El Ashkar ¹, Jennifer A. Perry⁴, Prathiba Jayaguru ¹¹, Laura Barreyro ¹¹, Anna Kuchnio ¹², Nicolas Darville ¹³, Daniel Krosky ⁹, Gregor Urbanietz¹, Bie Verbist ¹⁴, James P. Edwards ¹⁵, Glenn S Cowley ¹⁶, Robert Kirkpatrick⁷, Ruth Steele ⁹, Lucille Ferrante ¹⁷, Christina Guttke ¹¹, Nikki Daskalakis ¹¹, E Christine Pietsch ⁷, David Matthew Wilson ¹⁸, Ricardo M. Attar¹⁹, Yusri A Elsayed ²⁰, Eric S Fischer ⁴, Jan Jacob Schuringa ²¹, Scott A Armstrong⁴, Kathryn Packman ²², Ulrike Philippar ¹²

¹Janssen R&D, Beerse, Belgium.

²FoRx Therapeutics, France.

³Medicilon Inc., China.

⁴Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

⁵Universitätsmedizin Greifswald, Germany.

⁶Department of Experimental Hematology, UMCG, Groningen, Netherlands.

⁷Janssen R&D, Spring Hous, Pennsylvania, United States.

⁸Galapagos, Mechelen, Belgium.

⁹Janssen R&D, Spring House, Pennsylvania, United States.

¹⁰Johnson and Johnson R&D, Beerse, Belgium.

¹¹Janssen, Spring House, Pennsylvania, United States.

¹²Discovery Oncology, Janssen R&D, Beerse, Beerse, Belgium.

¹³Johnson & Johnson Innovative Medicine, Beerse, Belgium.

¹⁴Johnson&Johnson, Beerse, Belgium.

¹⁵Janssen, United States.

¹⁶Janssen R&D LLC, Spring House, Pennsylvania, United States.

¹⁷Janssen Research & Development, Spring House, Pennsylvania, United States.

¹⁸AstraZeneca, United Kingdom.

¹⁹Janssen Pharmaceuticals, Spring House, Pennsylvania, United States.

²⁰Janssen Research & Development, LLC, Spring House, Pennsylvania, United States.

²¹University Medical Center Groningen, Groningen, Netherlands.

²²Janssen Research and Development, Newton, Massachusetts, United States.

Corresponding Author: Ulrike Philippar

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 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) 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 anti-proliferative activity across several AML and 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 anti-proliferative activity in cell lines engineered with recently discovered mutations (MEN1M327I or MEN1T349M) that developed in patients refractory to the menin-KMT2A inhibitor revumenib. A co-crystal 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 (R/R) acute leukemia (NCT04811560), or in combination with AML-directed therapies (NCT05453903).

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-25)
연구진국외 연구진
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