Menin–MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers

Sep 24, 2026

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Encoded by the MEN1 gene, menin is an essential fusion protein for oncogenic transformation in mixed-lineage leukemia (MLL), driving acute leukemia development. Accumulating evidence indicates that blocking the high-affinity menin–MLL1 (KMT2A) interaction is effective against MLL-rearranged leukemia in vitro and in vivo. Recent findings also show tumor-suppressive activity of menin–MLL1 interaction inhibitors in distinct cancer types, supporting their promise as a therapeutic approach. This review summarizes recent progress, molecular mechanisms, and application prospects for acute leukemia and cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Menin and MEN1 gene in leukemia biology

Small molecule inhibitors targeting the menin–MLL1 interaction

Roles of menin in solid tumor carcinogenesis

Therapeutic prospects and future research directions

molecules Review Menin–MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers Qing Shi 1,2,†, Meiqi Xu 1,†, Zhijian Kang 2, Manjie Zhang 3,* and Yakun Luo 1, * Citation: Shi, Q.; Xu, M.; Kang, Z.; Zhang, M.; Luo, Y. Menin–MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers. Molecules 2023, 28, 3026. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/molecules28073026](10.3390/molecules28073026) Academic Editor: Wolfgang Sippl Received: 18 February 2023 Revised: 26 March 2023 Accepted: 27 March 2023 Published: 28 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 National Health Commission Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin 150001, China 2 Department of Urology, The Fourth Afﬁliated Hospital of Harbin Medical University, Harbin 150001, China 3 College of Pharmacy, Harbin Medical University, Harbin 150080, China * Correspondence: [zhangmj454@nenu.edu.cn](zhangmj454@nenu.edu.cn) (M.Z.); [luoyankun@hrbmu.edu.cn](luoyankun@hrbmu.edu.cn) (Y.L.)† These authors contributed equally to this work. Abstract: Encoded by the MEN1 gene, menin protein is a fusion protein that is essential for the oncogenic transformation of mixed-lineage leukemia (MLL) and leads to acute leukemia (AL) . Therefore, accumulating evidence has demonstrated that inhibition of the high-afﬁnity relationship between menin and mixed-lineage leukemia 1 (MLL1 and KMT2A) is an effective treatment for MLL-rearranged (MLL-r) leukemia in vitro and in vivo. Meanwhile, recent studies found that menin–MLL1 interaction inhibitors exhibited a ﬁrm tumor suppressive ability in speciﬁc cancer cells, such as prostate cancer, breast cancer, liver cancer, and lung cancer. Overall, it seems to serve as a novel therapeutic means for cancers. Herein, we review the recent progress in exploring the inhibitors of small molecule menin–MLL1 interactions. The molecular mechanisms of these inhibitors' functions and their application prospects in the treatment of AL and cancers are explored. Keywords: molecule inhibitor; menin-MLL1 complex; leukemia; cancer; therapeutics strategies 1. Introduction The MEN1 gene is one of the key pathogenic genes of multiple endocrine neoplasia 1 (MEN1) syndromes [1]. In 1988, the MEN1 gene was found in chromosome 11q13 [2], and it was positionally cloned in 1997 [3,4] . With a span of 9.8 kb and 10 exons, the position of the MEN1 gene is at chromosome 11q13 . Exon 1 and the distal part of exon 10 are non-coding sequences. It encodes the menin protein. The MEN1 gene has a wide expression proﬁle and a tissue-speciﬁc menin function, as proven in biochemical and genetic studies [5] . Menin is found to be an essential inﬂuencer in the pathogenesis of leukemia [6] . It has been demonstrated that menin is essential in the oncogenic transformation of fusion proteins in mixed-lineage leukemia (MLL), including MLL-ENL, MLL-AF4, MLL-AF6, and MLL-AF9, subsequently leading to acute leukemia (AL) . In the clinical experience of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), the MLL gene's rearrangement is commonly observed in chromosome translocation [7,8], with acute myeloid leukemia (AML) incidence of approximately 10% in adults and 70% in infants [9,10] . There is an unfavorable prognosis for leukemia patients suffering from MLL translocation, and they have poor responses to available therapeutic means. According to biochemical research, menin is related to histone methyltransferases (HNT) MLL1 and MLL2 in the tritho

FAQs

Why is the menin–MLL1 interaction considered a therapeutic target in leukemia?

Menin is essential for oncogenic transformation of MLL fusion proteins, which leads to acute leukemia. Inhibiting the high-affinity menin–MLL1 (KMT2A) interaction is described as an effective approach for MLL-rearranged leukemia in vitro and in vivo.

What kinds of cancers are reported to be affected by menin–MLL1 interaction inhibitors?

The text reports tumor-suppressive ability in specific solid cancer cells, including prostate, breast, liver, and lung cancers, in addition to acute leukemia contexts.

How does the article characterize the mechanism by which menin contributes to gene regulation?

It states that menin is related to histone methyltransferases in the trithorax family and that structural analysis supports direct binding to the N-terminus of MLL1 fusion proteins. This binding is critical for recruiting target genes such as MEIS1 and HOXA9.

Sep 24, 2026

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