What are the new molecules for menin inhibitors?

Introduction to Menin and Its Role

Biological Function of Menin
Menin is a nuclear scaffold protein encoded by the MEN1 gene that plays a pivotal role in regulating gene transcription through its interactions with epigenetic modulators and transcription factors. It functions as a multipurpose adaptor protein by binding to several partners, including members of the MLL (mixed-lineage leukemia) family, histone modifiers, and other chromatin regulators. This interaction helps to orchestrate the expression of critical gene clusters, such as HOX and MEIS1, which are central to cell differentiation and proliferation. Menin’s structural characteristics allow it to serve as an intermediary that conveys signals between chromatin modification systems and transcriptional machinery, thereby contributing to the maintenance of continual regulation of cellular processes.

Menin in Disease Context, Especially Cancer
Although menin has traditionally been viewed as a tumor-suppressor protein, its role is context-dependent. In several endocrine cancers such as those found in multiple endocrine neoplasia type 1 (MEN1), menin’s loss of function contributes to tumor formation. However, in other malignancies, particularly leukemias such as those driven by MLL rearrangements and NPM1 mutations, menin acts as an oncogenic cofactor. By binding to MLL fusion proteins, menin facilitates the aberrant transcription of genes critical for leukemogenesis. This duality in function not only underlines the importance of menin in normal physiology but also highlights its significance as a therapeutic target in cancers where its activity is deleterious. The oncogenic role has also been extended to other solid tumors, including prostate and breast cancers, indicating a broad spectrum of malignancies where dysregulated menin activity is implicated.

Development of Menin Inhibitors

Overview of Menin Inhibition
Targeting the menin-MLL interaction has emerged as a promising therapeutic approach because it directly interrupts a critical driver of oncogenic transcription. Menin inhibitors are small molecules designed to bind to menin with high affinity and specificity, thereby blocking its interaction with MLL fusion proteins. The disruption of this interaction leads to the suppression of HOX/MEIS1-related gene expression, reversing the malignant phenotype of the cells. The therapeutic rationale behind menin inhibition is that by stopping this protein–protein interaction (PPI), one can profoundly affect the transcriptional program that sustains leukemic cell survival and proliferation.

Historical Perspective on Menin Inhibitors
Historically, the concept of interfering with protein–protein interactions was long considered challenging due to the large and flat binding interfaces. Nonetheless, advancements in structural biology and high-throughput screening eventually facilitated the discovery of small molecules capable of inhibiting the menin-MLL interaction. Early compounds such as MI-2 and its derivatives laid the groundwork for this field by demonstrating that it was possible to achieve significant inhibition using micromolar to nanomolar concentrations. Subsequent medicinal chemistry efforts greatly improved the potency and pharmacokinetic profiles of these inhibitors, initiating a new era of research into selective menin inhibitors. Over time, compounds evolved from reversible to covalent inhibitors, expanding not only our mechanistic understanding but also the clinical potential of these agents.

New Molecules for Menin Inhibition

Recently Developed Molecules
In recent years, a variety of new molecules have been developed that demonstrate improved potency, selectivity, and favorable pharmacokinetic profiles. These compounds have been designed using structure‐based drug design approaches that exploit detailed crystallographic data of human menin in complex with its interacting partners. Some of the most prominent and novel molecules include:

• Revumenib (formerly known as SNDX-5613):
Revumenib is among the most advanced menin inhibitors in clinical development. It is an orally administered, small-molecule inhibitor that has demonstrated remarkable activity in early-phase clinical trials in patients with acute myeloid leukemia (AML) harboring menin-dependent alterations such as MLL rearrangements and NPM1 mutations. Its design capitalizes on the interruption of the menin-MLL interaction, leading to downregulation of HOX and MEIS1 gene transcription. Clinical data have shown promising remission rates with deep molecular responses, making it a frontrunner in menin inhibition strategies.

• Ziftomenib (also known as KO-539):
Another novel menin inhibitor is ziftomenib, which has also entered clinical trials. Ziftomenib is designed to block the interaction between menin and MLL fusion proteins, thereby affecting oncogenic signaling pathways in leukemic cells. Early-phase studies have indicated that ziftomenib, as a monotherapy or in combination with agents like venetoclax, delivers synergistic antileukemic effects in patients, especially those with MLL-rearranged and NPM1-mutated AML.

• DS-1594b:
This molecule is an orally bioavailable inhibitor that specifically targets the menin-MLL interaction. DS-1594b has been characterized by its ability to bind menin and prevent its interaction with MLL, leading to disruption of oncogenic gene expression programs. Preclinical studies have supported its activity in MLL-rearranged leukemic models, identifying DS-1594b as a promising candidate for further clinical evaluation.

• BMF-219:
BMF-219 stands out as a covalent inhibitor of menin that has been developed with a novel chemical scaffold. Unlike reversible inhibitors, BMF-219 forms a covalent bond with its target, leading to sustained inhibition even after the drug has been cleared from circulation. Preclinical and early clinical data, such as those presented in the COVALENT-101 clinical trial, demonstrate its potent antitumor activity in various liquid and solid tumor models, as well as promising signals in both oncologic and metabolic indications (e.g., diabetes).

• MI-463 and MI503:
Based on a cyanoindole ring connected to a thienopyrimidine core, these molecules represent innovative structural classes emerging from extensive lead optimization. Both MI-463 and MI503 exhibit IC50 values of approximately 15 nM in biochemical assays, indicating high potency. Their design is derived from crystallographic studies of the human menin complex, and they have demonstrated favorable pharmacological profiles in traditional preclinical studies.

• MIV6 and MIV6R:
Derived from hydroxy- and aminomethylpiperidine scaffolds, these compounds were developed through high-throughput screening (HTS) and subsequent structure-based design refinement. The prototype MIV6 showed an IC50 around 56 nM, while an optimized analog, MIV6R, maintains similar potency and robust effects on the menin-MLL interaction. These molecules help validate that a diverse range of chemical scaffolds can successfully inhibit menin.

• Macrocyclic peptidomimetics (e.g., MCP1):
Zhou and colleagues pioneered an alternative approach using macrocyclic peptidomimetics that mimic the native binding motif of MLL on menin. Although such compounds have high potency (with IC50 values in the 5–20 nM range), their high molecular weight and pharmacokinetic liabilities have hindered further clinical development. Nevertheless, they remain an important proof of concept for targeting large PPI interfaces.

• M123:
Using both pharmacophore-based and structure-based screening methods, M123 has been identified as a potent inhibitor with an IC50 of approximately 5 nM. Its capacity to inhibit the growth of MLL-rearranged leukemia cells makes it a compelling candidate for further development, embodying the advantages of integrating computational drug discovery techniques into menin inhibitor design.

• Additional molecules from patent literature:
Several patent documents have highlighted novel formulations, crystalline forms, and solvate versions of menin inhibitors designed to optimize drug-like properties and bioavailability. For example, patent references describe various inhibitors of menin-MLL interactions, many of which incorporate unique chemical modifications intended to improve potency, selectivity, and pharmacodynamic profiles. Such proprietary molecules often combine innovations in scaffold design with modifications that facilitate improved tissue penetration, stability, and safety profiles in vivo.

• Other clinical candidates:
A list compiled by several news sources mentions additional menin inhibitors in development, including BN-104, Mi-003, BNM-1192, D0060-319, and DS-M1. Although these molecules differ in chemical structure, they share the common mechanism of disrupting the menin-MLL fusion protein interaction and are currently undergoing various stages of preclinical and early clinical evaluation.

Mechanisms of Action
The commonality among these novel molecules is their ability to interfere with the protein–protein interaction between menin and MLL or MLL-fusion proteins. This interaction is crucial for the maintenance of an oncogenic gene expression program—most notably the sustained transcription of HOX genes and MEIS1—that drives the proliferation of leukemic cells. An in-depth structural analysis of menin has revealed “hotspot” regions responsible for its interaction with MLL. The new molecules have been designed to target these hotspots by either mimicking the natural binding motif of MLL, thereby competing for binding, or by covalently modifying critical residues in the menin binding pocket.

For instance, studies on the MI series (such as MI-463, MI503, and MI-2) have shown that these molecules can effectively emulate key hydrophobic interactions required for MLL binding, which is achieved by incorporating motifs like the cyanoindole ring or aminomethylpiperidine residues into their structure. Other compounds, such as revumenib and DS-1594b, bind to menin in a manner that induces a conformational change unfavorable for interactions with MLL, leading to rapid degradation of downstream oncogenic signals. Covalent inhibitors like BMF-219 irreversibly bind to the menin protein, ensuring prolonged inhibition even after systemic clearance, a feature highly desirable in aggressive cancers where continuous signaling is a primary driver of disease.

Mechanistic evaluations have typically employed crystallographic studies to observe the binding modes of these inhibitors. For example, co-crystal structures of menin with inhibitors like MI2 allowed scientists to delineate the key residues involved in binding and to subsequently design analogs with enhanced potency. Moreover, biochemical assays measuring IC50 values and functional assays such as inhibition of HOX gene expression in leukemic cell lines have validated these mechanisms. In preclinical models, these inhibitors have been shown to decrease the proliferation of leukemic cells by downregulating HOX/MEIS1 transcription and promoting differentiation.

Preclinical and Clinical Evaluation
The promising in vitro data for many of these new molecules are complemented by robust preclinical in vivo studies. In murine models of acute myeloid leukemia (AML) harboring MLL rearrangements or NPM1 mutations, inhibitors such as revumenib and ziftomenib have demonstrated significant antileukemic efficacy. For instance, revumenib has been associated with overall response rates of over 50% and complete remission in a subset of heavily pretreated patients, with a large proportion achieving minimal residual disease negativity after just a few cycles.

Ziftomenib has shown similar efficacy in early-phase clinical trials, particularly when combined with other agents like venetoclax. The synergistic effect of these combinations underscores the potential for menin inhibitors not only as monotherapies but also in combination regimens that can overcome resistance and improve outcomes. In addition, DS-1594b has effectively blocked the menin-MLL interaction in both cell lines and animal models, demonstrating its capacity to impede tumor growth via targeted disruption of oncogenic signaling cascades.

Preclinical safety evaluations have also been encouraging. For example, compounds like MI-463 and MI503 have been optimized not just for potency but also for pharmacokinetic properties, ensuring that they have acceptable bioavailability, metabolic stability, and minimal off-target effects. Their progression through standard preclinical toxicology assessments has paved the way for their inclusion in early-phase clinical trials. Similarly, BMF-219’s covalent binding mode has shown that sustained inhibition of menin is achievable without considerable adverse effects, further warranting clinical investigation.

Moreover, several patent documents emphasize advances in formulation and chemical modifications designed to enhance the delivery and stability of these inhibitors. The evolving landscape of menin inhibitors is characterized by an iterative process where each generation of compounds builds upon the successes and limitations of its predecessors. This is also exemplified by the development of macrocyclic peptidomimetics and structure-based designs like M123, which offer not only extraordinary potency (with IC50 values reaching down to 5 nM) but also a deepened understanding of the molecular interactions between menin and its inhibitors.

Therapeutic Potential and Challenges

Potential Applications in Oncology
The potential clinical applications of these new menin inhibitors are extensive, primarily targeting hematological malignancies wherein aberrant menin activity is a key driver of oncogenesis. In leukemias characterized by MLL rearrangements and NPM1 mutations, menin inhibitors have shown significant promise. The downregulation of the HOX/MEIS1 gene signature in these cancers translates into reduced cell proliferation, induced differentiation, and increased apoptosis of malignant cells, offering a novel therapeutic strategy to achieve remission in patients who have failed conventional therapies.

Furthermore, emerging data suggest that menin inhibitors may have applications beyond hematological malignancies. For example, preclinical evidence implies that certain solid tumors, such as prostate, breast, and liver cancers, might also benefit from menin inhibition due to the tumor-promoting nature of menin in specific cellular contexts. Additionally, the dual role of menin in metabolism and cell proliferation has sparked interest in exploring its inhibition for metabolic diseases like diabetes, as seen with candidates like BMF-219. This breadth of potential uses underscores the transformative impact that effective menin inhibition could have on patient care by targeting a common node in divergent disease pathways.

Challenges in Drug Development
Despite the significant promise, several challenges remain in the clinical development of menin inhibitors. One major hurdle is ensuring the selectivity of these agents. Given that menin interacts with multiple partners and modulates various transcriptional programs, off-target effects could lead to undesirable toxicities. For instance, while the inhibition of the menin-MLL interaction is beneficial in leukemias, prolonged disruption of other menin-dependent transcriptional pathways may affect normal cellular functions. Additionally, the dose-limiting toxicities observed in early-phase trials underscore the need for precise dose optimization and careful patient selection.

Furthermore, resistance remains a challenge for all targeted therapies, and menin inhibitors are no exception. Acquired point mutations in the menin binding pocket or activation of compensatory signaling pathways can lead to clinical resistance. Therefore, ongoing research is focused on elucidating the resistance mechanisms and developing next-generation inhibitors that can either overcome or avert resistance. Combination strategies, for example by pairing menin inhibitors with agents targeting complementary pathways such as FLT3, BCL2, or XPO1, are being actively investigated as a means to enhance efficacy and prolong patient responses.

Another significant challenge is the pharmacokinetic profile of these agents. Many of the early inhibitors required improvements in bioavailability, metabolic stability, and tissue penetration. The evolution from reversible inhibitors to covalent inhibitors, as seen with BMF-219, represents a deliberate effort to surmount these limitations. However, ensuring that these compounds maintain high potency without compromising safety is an ongoing area of research.

Lastly, the design of clinical trials to assess these novel molecules presents its own set of hurdles. Given the heterogeneity of cancers that might benefit from menin inhibition, adaptive and basket trial designs are being considered that allow for the simultaneous evaluation of multiple tumor types and molecular subtypes. Such innovative clinical trial designs are essential for efficient patient stratification and for obtaining meaningful data on treatment efficacy.

Future Research Directions
Looking ahead, the field of menin inhibition is expected to focus on several key areas:

• Optimizing Combination Therapies:
Future research will likely intensify efforts to combine menin inhibitors with other targeted agents. Studies are already evaluating combinations with FLT3 inhibitors, BCL2 inhibitors like venetoclax, and possibly immune checkpoint inhibitors. The rationale is that combination regimens might overcome resistance mechanisms and synergistically improve patient outcomes.

• Refinement of Chemical Scaffolds:
Continued medicinal chemistry efforts will aim to refine existing scaffolds and develop entirely new chemical classes. The goal is to achieve even greater selectivity, potency, and better pharmacokinetic properties. For example, further modifications of the thienopyrimidine-based scaffolds (MI463 and MI503) or the piperidine-derived MIV6 analogs could yield next-generation compounds with improved efficacy and minimized side effects.

• Development of Covalent Inhibitors:
Given the sustained effect observed with covalent binding, further exploration into irreversible inhibitors like BMF-219 is anticipated. These compounds potentially offer longer durations of action and more robust inhibition of menin’s oncogenic activity, but require careful management of off-target reactivity and toxicity.

• Resistance Mechanism Elucidation:
Investigating the molecular basis of acquired resistance remains a priority. Understanding how mutations within menin or alterations in downstream signaling contribute to resistance will inform the development of inhibitors with broader efficacy or guide rational combination strategies that sidestep resistance.

• Expanded Therapeutic Indications:
While the current focus is on leukemias, research is beginning to explore the utility of menin inhibitors in treating solid tumors and metabolic diseases. Preclinical models have shown that menin modulation may affect tumor microenvironment, hormonal signaling, and even beta cell function. As such, future trials may include patient populations with a diverse range of conditions linked to aberrant menin activity.

• Advanced Drug Delivery Systems:
Integrating advanced drug delivery systems such as nanoparticle-based formulations or conjugate technologies might boost the therapeutic index of menin inhibitors. These delivery methods could enhance tissue targeting, reduce systemic toxicity, and provide more controlled release, thereby improving the overall clinical utility of these compounds.

• Biomarker Discovery and Patient Stratification:
Identifying reliable biomarkers to gauge menin inhibitor response is another critical area. Companion diagnostics that accurately determine menin dependency in tumors will be vital for patient selection and for monitoring therapeutic responses during clinical trials. Such biomarkers could include specific gene expression signatures (e.g., HOX/MEIS1 levels) or even mutations in the MEN1 binding domain that predict sensitivity or resistance.

Conclusion
In summary, the landscape of menin inhibitors has evolved remarkably over the past few years, shifting from early-stage proof-of-concept molecules to a diverse portfolio of novel agents that have entered advanced clinical evaluations. Newly developed molecules such as revumenib (SNDX-5613), ziftomenib (KO-539), DS-1594b, BMF-219, MI463, MI503, MIV6/MIV6R, and macrocyclic peptidomimetics (e.g., MCP1) are at the forefront of this field. These inhibitors share a common mechanism of action: the disruption of the interaction between menin and MLL fusion proteins, leading to the suppression of oncogenic gene transcription programs that drive leukemogenesis. Preclinical studies have confirmed their high potency—often in the nanomolar range—and favorable pharmacodynamics, while early-phase clinical trials, particularly for revumenib and ziftomenib, have revealed promising response rates in patients with AML harboring MLL rearrangements or NPM1 mutations.

Despite these advances, significant challenges remain. Key areas of concern include ensuring selective inhibition of the pathogenic menin interactions without disturbing its critical roles in normal cellular functions, overcoming the emergence of resistance mutations, and optimizing the pharmacokinetic profiles of these compounds to maximize therapeutic benefit. Ongoing research is addressing these issues through combination therapies, the development of covalent inhibitors, innovative clinical trial designs, and the exploration of novel chemical scaffolds. Additionally, the potential expansion of menin inhibition into the realm of solid tumors and metabolic disease underscores the broad therapeutic promise of these agents.

The future of menin inhibitors lies in a multidimensional research strategy that incorporates advanced medicinal chemistry, rigorous preclinical evaluation, and innovative clinical trial designs. By combining these approaches, researchers are poised to not only enhance the efficacy of menin-targeted therapies but also to ensure that they are safe and effective for a wide spectrum of patients. The continued evolution of this field, characterized by detailed structural insights and iterative design improvements, heralds a new era in precision oncology in which the disruption of critical protein–protein interactions such as menin-MLL may offer transformative benefits for patients with otherwise difficult-to-treat cancers.

In conclusion, the new molecules for menin inhibition represent an excellent convergence of advanced drug design, robust preclinical validation, and early clinical promise. They tackle a crucial translational challenge by targeting the menin-MLL interaction—an essential driver of leukemogenesis and, possibly, other malignancies. As further clinical data emerge and combination strategies are refined, these novel agents are expected to play a central role in future cancer therapy, offering hope for improved outcomes in both hematological and potentially solid tumors. The meticulous research documented in the synapse references illustrates the promising trajectory for these therapeutic agents and underscores the need for continued innovation in this field.