Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia

doi:10.3969/j.issn.1674-8115.2024.10.011

Abstract

Abstract:

Acute leukemias caused by mixed lineage leukemia (MLL) gene rearrangements (MLL-r) are characterized by high invasiveness and a poor prognosis, with few specific treatment options available. MLL protein is essential in embryonic development and hematopoiesis. It exhibits histone methyltransferase activity and can interact with various proteins through its functional domains, thus regulating downstream target gene expression through epigenetic modifications. MLL-r leads to the formation of MLL fusion proteins (MLL-FPs), in which the C-terminal is replaced by fusion partner proteins; over 100 such partner proteins have been identified to date. In numerous studies of the molecular mechanism, Menin serves as an important cofacter in the leukemogenesis of MLL-FPs and participates in forming the key complex when interacting with the N terminal of MLL protein, resulting in the disregulation of certain targeted genes, which makes the development of Menin-MLL inhibitors theoretically possible. To date, several small molecules have been identified that inhibit Menin-MLL interaction, including thienopyrimidine derivatives, piperidine derivatives, pyrimidine derivatives, and macrocyclic mimic peptides. Based on these prototypes, at least seven drugs are currently undergoing clinical evaluation, with some promising preliminary data regarding safety, tolerability, and efficacy. This review summarizes the structure and function of MLL, the mechanism of the occurrence of MLL-r leukemia, and current Menin-MLL inhibitors tested in MLL-r leukemia.

Key words: MLL-rearranged leukemia, Menin, targeted therapy, Menin-MLL inhibitor

CLC Number:

R733.71

FANG Xinyue, SHI Lan, XIA Siyi, WANG Jiaxuan, WU Yingli, HE Kejun. Research progress in Menin-MLL interaction and its inhibitors in MLL-rearranged leukemia[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1287-1298.

Figures/Tables 5

TrendMD

References 67

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Drug	Reference	Phase	Designment	Status/ Results
Revumenib (SNDX-5613)	NCT04065399 (AUGMENT-101)	Ⅰ	AML, ALL	n=94, discontinuation: 6.4%
	NCT04065399 (AUGMENT-101)	Ⅱ	r/r AML with MLL-r, r/r ALL with MLL-r, r/r AML with mNPM1	n=57, ORR=63.2%, CRc=43.9% (r/r AML with MLL-r and r/r ALL with MLL-r); n=13, ORR=46.2%, CRc=38.5% (pediatric r/r AML with MLL-r and r/r ALL with MLL-r)
	NCT05360160 (SAVE)	Ⅰ/Ⅱ	r/r AML with MLL-r/mNPM1/NUP98-r: ASTX727/venetoclax	n=9, ORR=100%, CRc=78%
	NCT05326516 (AUGMENT-102)	Ⅰ	r/r AML, ALL with MLL-r/mNPM1/NUP98-r: Chemo Regimen 1, Chemo Regimen 2	n=15, CRc=33% (Chemo Regimen 2)
	NCT03013998 (BEAT-AML)	Ⅰ	AML with MLL-r/mNPM1, age≥60 years: venetoclax/azacitidine	n=13, CRc=100%
	ACTRN12621000439842	Ⅰ/Ⅱ	MRD⁺AML with MLL-r/mNPM1	Recruiting, unavailable
	NCT05886049	Ⅰ	AML with MLL-r/mNPM1: 7+3 chemo	Recruiting, unavailable
	NCT06222580	Ⅰ	r/r AML with MLL-r/mNPM1 FLT3 co-mutation: gilteritinib	Recruiting, unavailable
	NCT06226571	Ⅰ	AML with MLL-r/mNPM1/NUP98-r: intensive chemotherapy	Recruiting, unavailable
	NCT05761171	Ⅱ	Pediatric r/r ALL, AML with MLL-r: fludarabine	Recruiting, unavailable
	NCT06177067	Ⅰ	Pediatric or young adult r/r AML with MLL-r/mNPM1/NUP98-r: venetoclax/azacitidine	Recruiting, unavailable
	NCT05918913	Expanded	r/r acute leukemia with genetic alterations associated with HOXA overexpression	Recruiting, unavailable
Ziftomenib (KO-539)	NCT04067336 (KOMET-001)	Ⅰ	r/r AML with MLL-r/mNPM1	n=20, ORR=45%, CRc=40%
	NCT04067336 (KOMET-001)	Ⅱ	r/r AML with mNPM1	n=20, ORR=45%, CRc=40%
	NCT05735184 (KOMET-007)	Ⅰ	AMLwith MLL-r/mNPM1: venetoclax & azacitidin, venetoclax, 7+3 chemo	n=9, ORR=78%, CRc=67% (venetoclax & azacitidin); n=5, CRc=100% (7+3 chemo)
	NCT06001788 (KOMET-008)	Ⅰ	r/r AML with MLL-r/mNPM1: FLAG-IDA, LD-AraC + gilteritinib (FLT3 co-mutation)	Recruiting, unavailable
	NCT05848687	Ⅰ/Ⅱ	Infant ALL	Recruiting, unavailable
	NCT05738538	Expanded	ALL with appropriate mutations, or AML with mNPM1	Recruiting, unavailable
Icovamenib (BMF-219)	NCT05153330 (COVALENT-101)	Ⅰ	r/r AML, ALL, DLBCL, MM, CLL	n=5, CRc=40% (r/r AML)
Emilumenib (DS-1594)	NCT04752163	Ⅰ	r/r AML, ALL	Completed, unavailable
Emilumenib (DS-1594)	NCT04752163	Ⅱ	r/r AML with MLL-r/mNPM1: venetoclax & azacitidine. r/r ALL with MLL-r: mini-HCVD	Completed, unavailable
DSP-5336	NCT04988555	Ⅰ	r/r AML, ALL	n=6, CRc=33.3%
DSP-5336	NCT04988555	Ⅱ	r/r AML with MLLr, an r/r AML with mNPM1	n=6, CRc=33.3%
JNJ-75276617	NCT04811560	Ⅰ/Ⅱ	r/r AML, ALL with MLL-r/mNPM1	n=41, CRc=29.2%
JNJ-75276617	NCT05453903	Ⅰ	AML with MLL-r/mNPM1: venetoclax, azacitidine or 7+3 chemo	Recruiting, unavailable
BN-104	NCT06052813	Ⅰ/Ⅱ	r/r AML, ALL	Recruiting, unavailable

Drug	Reference	Phase	Designment	Status/ Results
Revumenib (SNDX-5613)	NCT04065399 (AUGMENT-101)	Ⅰ	AML, ALL	n=94, discontinuation: 6.4%
	NCT04065399 (AUGMENT-101)	Ⅱ	r/r AML with MLL-r, r/r ALL with MLL-r, r/r AML with mNPM1	n=57, ORR=63.2%, CRc=43.9% (r/r AML with MLL-r and r/r ALL with MLL-r); n=13, ORR=46.2%, CRc=38.5% (pediatric r/r AML with MLL-r and r/r ALL with MLL-r)
	NCT05360160 (SAVE)	Ⅰ/Ⅱ	r/r AML with MLL-r/mNPM1/NUP98-r: ASTX727/venetoclax	n=9, ORR=100%, CRc=78%
	NCT05326516 (AUGMENT-102)	Ⅰ	r/r AML, ALL with MLL-r/mNPM1/NUP98-r: Chemo Regimen 1, Chemo Regimen 2	n=15, CRc=33% (Chemo Regimen 2)
	NCT03013998 (BEAT-AML)	Ⅰ	AML with MLL-r/mNPM1, age≥60 years: venetoclax/azacitidine	n=13, CRc=100%
	ACTRN12621000439842	Ⅰ/Ⅱ	MRD⁺AML with MLL-r/mNPM1	Recruiting, unavailable
	NCT05886049	Ⅰ	AML with MLL-r/mNPM1: 7+3 chemo	Recruiting, unavailable
	NCT06222580	Ⅰ	r/r AML with MLL-r/mNPM1 FLT3 co-mutation: gilteritinib	Recruiting, unavailable
	NCT06226571	Ⅰ	AML with MLL-r/mNPM1/NUP98-r: intensive chemotherapy	Recruiting, unavailable
	NCT05761171	Ⅱ	Pediatric r/r ALL, AML with MLL-r: fludarabine	Recruiting, unavailable
	NCT06177067	Ⅰ	Pediatric or young adult r/r AML with MLL-r/mNPM1/NUP98-r: venetoclax/azacitidine	Recruiting, unavailable
	NCT05918913	Expanded	r/r acute leukemia with genetic alterations associated with HOXA overexpression	Recruiting, unavailable
Ziftomenib (KO-539)	NCT04067336 (KOMET-001)	Ⅰ	r/r AML with MLL-r/mNPM1	n=20, ORR=45%, CRc=40%
	NCT04067336 (KOMET-001)	Ⅱ	r/r AML with mNPM1	n=20, ORR=45%, CRc=40%
	NCT05735184 (KOMET-007)	Ⅰ	AMLwith MLL-r/mNPM1: venetoclax & azacitidin, venetoclax, 7+3 chemo	n=9, ORR=78%, CRc=67% (venetoclax & azacitidin); n=5, CRc=100% (7+3 chemo)
	NCT06001788 (KOMET-008)	Ⅰ	r/r AML with MLL-r/mNPM1: FLAG-IDA, LD-AraC + gilteritinib (FLT3 co-mutation)	Recruiting, unavailable
	NCT05848687	Ⅰ/Ⅱ	Infant ALL	Recruiting, unavailable
	NCT05738538	Expanded	ALL with appropriate mutations, or AML with mNPM1	Recruiting, unavailable
Icovamenib (BMF-219)	NCT05153330 (COVALENT-101)	Ⅰ	r/r AML, ALL, DLBCL, MM, CLL	n=5, CRc=40% (r/r AML)
Emilumenib (DS-1594)	NCT04752163	Ⅰ	r/r AML, ALL	Completed, unavailable
Emilumenib (DS-1594)	NCT04752163	Ⅱ	r/r AML with MLL-r/mNPM1: venetoclax & azacitidine. r/r ALL with MLL-r: mini-HCVD	Completed, unavailable
DSP-5336	NCT04988555	Ⅰ	r/r AML, ALL	n=6, CRc=33.3%
DSP-5336	NCT04988555	Ⅱ	r/r AML with MLLr, an r/r AML with mNPM1	n=6, CRc=33.3%
JNJ-75276617	NCT04811560	Ⅰ/Ⅱ	r/r AML, ALL with MLL-r/mNPM1	n=41, CRc=29.2%
JNJ-75276617	NCT05453903	Ⅰ	AML with MLL-r/mNPM1: venetoclax, azacitidine or 7+3 chemo	Recruiting, unavailable
BN-104	NCT06052813	Ⅰ/Ⅱ	r/r AML, ALL	Recruiting, unavailable

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