Article
作者: Fischer, Eric S ; Querolle, Olivier ; Ferrante, Lucille ; Shaffer, Paul L ; Jayaguru, Prathiba ; Eyassu, Filmon ; Dai, Xuedong ; Philippar, Ulrike ; Kirkpatrick, Robert ; Jacobs, Frank ; Perner, Florian ; Thuring, Jan Willem ; Schuringa, Jan Jacob ; Marien, Ann ; Ashkar, Sara El ; Krosky, Daniel ; Verbist, Bie ; Attar, Ricardo M ; Wenge, Daniela V ; Pande, Vineet ; Cutler, Jevon A ; Daskalakis, Nikki ; Urbanietz, Gregor ; Pietsch, E Christine ; Yue, Hong ; Edwards, James P ; Elsayed, Yusri A ; Verstraeten, Karin ; Kuchnio, Anna ; Jin, Cyrus ; Cowley, Glenn S ; Steele, Ruth ; Barreyro, Laura ; Vinken, Petra ; Guttke, Christina ; Wilson, David Matthew ; Darville, Nicolas ; Armstrong, Scott A ; Hogeling, Shanna M ; Keersmaekers, Vikki ; Bhogal, Balpreet ; Kwon, Min Chul ; Packman, Kathryn ; Verhulst, Tinne ; Perry, Jennifer A ; Cai, Wei ; Goffin, Dries
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).