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

被引：15

作者：

Kwon, Min Chul ^{[1
]}

Thuring, Jan Willem ^{[2
]}

Querolle, Olivier ^{[2
]}

Dai, Xuedong ^{[3
]}

Verhulst, Tinne ^{[1
]}

Pande, Vineet ^{[2
]}

Marien, Ann ^{[1
]}

Goffin, Dries ^{[1
]}

Wenge, Daniela, V ^{[4
,5
,6
]}

Yue, Hong ^{[7
,8
]}

Cutler, Jevon A. ^{[4
,5
,6
]}

Jin, Cyrus ^{[7
,8
]}

Perner, Florian ^{[4
,5
,6
]}

Hogeling, Shanna M. ^{[9
]}

Shaffer, Paul L. ^{[10
]}

Jacobs, Frank ^{[2
]}

Vinken, Petra ^{[2
]}

Cai, Wei ^{[3
]}

Keersmaekers, Vikki ^{[1
]}

Eyassu, Filmon ^{[1
]}

Bhogal, Balpreet ^{[10
]}

Verstraeten, Karin ^{[1
]}

El Ashkar, Sara ^{[1
]}

Perry, Jennifer A. ^{[4
,5
,6
]}

Jayaguru, Prathiba ^{[11
]}

Barreyro, Laura ^{[11
]}

Kuchnio, Anna ^{[1
]}

Darville, Nicolas ^{[2
]}

Krosky, Daniel ^{[10
]}

Urbanietz, Gregor ^{[2
]}

Verbist, Bie ^{[12
]}

Edwards, James P. ^{[10
]}

Cowley, Glenn S. ^{[10
]}

Kirkpatrick, Robert ^{[10
]}

Steele, Ruth ^{[10
]}

Ferrante, Lucille ^{[12
]}

Guttke, Christina ^{[11
]}

Daskalakis, Nikki ^{[13
]}

Pietsch, E. Christine ^{[14
]}

Wilson, David M. ^{[2
]}

Attar, Ricardo ^{[11
]}

Elsayed, Yusri ^{[14
]}

Fischer, Eric S. ^{[7
,8
]}

Schuringa, Jan Jacob ^{[9
]}

Armstrong, Scott A. ^{[4
,5
,6
]}

Packman, Kathryn ^{[15
]}

Philippar, Ulrike ^{[1
]}

机构：

[1] Janssen R&D, Discovery Oncol, Turnhoutseweg 30, B-2340 Beerse, Belgium

[2] Janssen R&D, Discovery Prod Dev & Supply, Beerse, Belgium

[3] Janssen R&D, Discovery Prod Dev & Supply, Shanghai, Peoples R China

[4] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA

[5] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA

[6] Harvard Med Sch, Boston, MA USA

[7] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA

[8] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Expt Hematol, Groningen, Netherlands

[10] Janssen R&D, Discovery Prod Dev & Supply, Spring House, PA USA

[11] Janssen R&D, Translat Res, Spring House, PA USA

[12] Janssen R&D, TMEDS, Beerse, Belgium

[13] Janssen R&D, Early Dev, Spring House, PA USA

[14] Janssen R&D, Discovery Oncol, Spring House, PA USA

[15] Janssen R&D, Early Dev, Cambridge, MA USA

来源：

BLOOD | 2024年 / 144卷 / 11期

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; LONG-TERM EXPANSION; GENE-EXPRESSION PROFILE; EX-VIVO ASSAYS; MENIN-MLL; CYTOPLASMIC NUCLEOPHOSMIN; SELF-RENEWAL; AML; TRANSFORMATION; MODELS;

D O I：

10.1182/blood.2023022480

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 (MEN1(M327I) or MEN1(T349M)) 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).

引用

页码：1206 / 1220

页数：15

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