Menin inhibitors are a new class of drugs developed to treat certain cancers. These agents interfere with specific protein interactions that drive cancer cell growth. This targeted approach focuses on the unique vulnerabilities of cancerous cells, aiming to offer more precise treatment options than therapies that broadly affect all rapidly dividing cells.
What Menin Inhibitors Are
Menin is a protein encoded by the MEN1 gene, playing a role in regulating gene expression and cell development. It functions as a “scaffold protein,” helping bring other proteins together to control how genes are turned on or off. While menin acts as a tumor suppressor in endocrine glands, preventing uncontrolled cell growth, it supports cancer cell survival in certain cancers. This dual function arises from its ability to interact with many different proteins and influence various cellular processes.
Menin inhibitors work by blocking the interaction between menin and other specific proteins. In cancer, this often involves disrupting the binding between menin and proteins like the KMT2A fusion protein or mutated NPM1 proteins. By preventing these interactions, menin inhibitors interfere with the aberrant gene expression programs that allow cancer cells to grow. This disruption can lead to the differentiation and eventual death of cancer cells, without significantly harming normal, healthy cells.
Treating Cancer with Menin Inhibitors
Menin inhibitors are being investigated for treating acute leukemias, specifically Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). They are particularly relevant for leukemias with specific genetic abnormalities, such as rearrangements in the KMT2A gene (formerly MLL) or mutations in the NPM1 gene. Approximately 5-10% of all acute leukemias involve KMT2A rearrangements, often associated with less favorable outcomes. NPM1 mutations are even more common, found in 20-30% of adult AML cases.
In these specific leukemias, cancer cells become dependent on menin for survival and uncontrolled proliferation. For instance, KMT2A gene rearrangements create fusion proteins that rely on menin to activate genes like HOX and MEIS1, driving leukemia development. Similarly, in NPM1-mutated AML, the mutated NPM1 protein interacts with KMT2A and menin, leading to the overexpression of HOXA9 and MEIS1, promoting leukemogenesis.
Menin inhibitors disrupt the binding between menin and these mutated or rearranged proteins. This action “switches off” the abnormal gene expression programs that cancer cells depend on. As a result, leukemia cells can no longer proliferate and are instead encouraged to mature or undergo programmed cell death. This targeted mechanism offers a new way to combat these difficult-to-treat leukemias by addressing their underlying genetic drivers.
Current Research and Clinical Progress
Menin inhibitors are in various stages of clinical development, with several compounds undergoing Phase 1, 2, and 3 clinical trials. Early trial results show encouraging activity in patients with relapsed or refractory acute leukemias, particularly those with KMT2A rearrangements or NPM1 mutations. For example, revumenib (SNDX-5613) and ziftomenib (KO-539) have demonstrated promising efficacy and manageable safety profiles in initial studies. JNJ-75276617 also showed early clinical activity in a Phase 1 trial, reducing bone marrow disease burden in 71% of evaluable patients with relapsed or refractory acute leukemias.
They are being explored as single agents and in combination with other therapies. Researchers are studying their use alongside standard chemotherapy or venetoclax-based regimens to enhance treatment effectiveness. The ability of menin inhibitors to downregulate HOX and MEIS1 genes suggests they could help overcome resistance to venetoclax in AML. While still investigational, these compounds hold promise for patients with historically challenging leukemias, potentially transforming future patient care.