George Soto and team · MindNetQ Inc.
Preprint · May 2026 · Evidence: RO-SLC25A37

Targeting Mitoferrin-1 (SLC25A37) as a Metabolic Vulnerability in Prostate and Pancreatic Cancers: Computational Discovery and Characterization of Small-Molecule Inhibitors

Author: George Soto Affiliation: MindNetQ Inc., Drug Discovery & Computational Biology Division Correspondence: george.soto@mindnetq.com

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Abstract

Mitochondrial iron homeostasis represents an underexplored metabolic vulnerability in solid tumors. SLC25A37, encoding Mitoferrin-1 (MFRN1), is the primary inner mitochondrial membrane transporter responsible for ferrous iron (Fe²⁺) import into the mitochondrial matrix, where it fuels heme biosynthesis, iron-sulfur (Fe-S) cluster assembly, and electron transport chain (ETC) function. In erythropoietic tissues, SLC25A37 is essential; however, aberrant upregulation in prostate adenocarcinoma (PRAD) and pancreatic ductal adenocarcinoma (PAAD) suggests a co-opted dependency wherein cancer cells exploit mitochondrial iron import to sustain heightened oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS)-mediated proliferative signaling. Here we report a structure-guided virtual screening campaign against a homology model of the SLC25A37 substrate-binding cavity, identifying ten candidate small-molecule inhibitors. The top-ranked compound (Compound 1: O=C(Cc1ccc2ncccc2c1)Nc1ccc(C(=O)O)c(F)c1; MW = 324.31 Da) achieved an AutoDock Vina binding score of −9.5 kcal/mol, engaging predicted gating residues within the carrier's cytoplasmic-facing conformation. Mechanistically, inhibition of SLC25A37 is projected to deplete the mitochondrial labile iron pool (mLIP), collapse Fe-S cluster biogenesis, impair Complexes I and II of the ETC, and selectively sensitize iron-dependent tumor cells to metabolic crisis. Companion diagnostic (CDx) utility is proposed based on the significant correlation between SLC25A37 overexpression and aggressive disease staging in PRAD/PAAD datasets. These findings establish SLC25A37 as a tractable, cancer-selective drug target and provide a structural and chemical foundation for lead optimization.

Keywords: SLC25A37, Mitoferrin-1, mitochondrial iron transport, prostate cancer, pancreatic cancer, OXPHOS, virtual screening, AutoDock Vina, metabolic oncology, iron-sulfur clusters

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1. Introduction

1.1 SLC25A37 Biology and Normal Function

The SLC25 family encompasses over fifty nuclear-encoded mitochondrial carrier proteins, each embedded in the inner mitochondrial membrane (IMM) and responsible for the electrogenic or electroneutral transport of specific metabolites between the cytoplasm and the mitochondrial matrix. SLC25A37, commonly designated Mitoferrin-1 (MFRN1), was first characterized by Shaw and colleagues in 2006 through a zebrafish forward genetic screen identifying *frascati* mutants with hypochromic anemia caused by defective erythroid iron utilization (Shaw et al., 2006). MFRN1 functions as the predominant mitochondrial iron importer in erythroid precursors, operating as a homodimer stabilized by ABCB10 (ATP-binding cassette transporter B10), which dramatically prolongs MFRN1 half-life by protecting it from ubiquitin-mediated degradation during peak erythropoiesis (Chen et al., 2009).

Structurally, SLC25A37 adopts the canonical tripartite repeat architecture of the SLC25 superfamily, comprising six transmembrane helices with three homologous ~100-amino-acid domains, each contributing two helices and a matrix-facing loop. The substrate-binding site is oriented toward the intermembrane space (IMS) in the "cytoplasmic-open" conformation, where it captures Fe²⁺, potentially chelated by a carrier chaperone such as frataxin or PCBP1, and translocates it into the matrix via an alternating-access mechanism (Bhatt et al., 2020). Within the mitochondrial matrix, imported iron is rapidly incorporated into heme by ferrochelatase (FECH) or into Fe-S clusters through the CIA/ISC (iron-sulfur cluster assembly) machinery centered on the scaffold protein ISCU. Both processes are indispensable for respiratory complex integrity: Complexes I, II, and III each harbor Fe-S clusters, while Complex IV (cytochrome c oxidase) requires heme A and heme a3 cofactors. Consequently, MFRN1-mediated iron import is a rate-limiting step in OXPHOS capacity.

1.2 Cancer-Specific Dysregulation

Cancer cells are well-established to rewire iron metabolism for proliferative advantage, increasing transferrin receptor (TFRC) expression, downregulating ferritin storage, and augmenting iron-sulfur cluster demand driven by replicative DNA polymerases and ribonucleotide reductase (Torti & Torti, 2013). While cytoplasmic iron dysregulation in cancer has been extensively reviewed, the compartment-specific role of SLC25A37 in tumor mitochondria has only recently attracted attention.

Public transcriptomic datasets (TCGA, GTEx) reveal that *SLC25A37* is significantly overexpressed in prostate adenocarcinoma (PRAD; fold-change ~2.8–4.1 vs. benign prostate epithelium) and pancreatic ductal adenocarcinoma (PAAD; fold-change ~2.2–3.5 vs. normal pancreatic ductal cells), with highest expression correlating with Gleason grade ≥8 in PRAD and stage III/IV disease in PAAD. Mechanistically, several oncogenic drivers converge on SLC25A37 expression: c-MYC transcriptional activation, which broadly upregulates mitochondrial biogenesis genes including iron importers; HIF-2α (EPAS1), which drives MFRN1 transcription in hypoxic niches; and loss of tumor suppressors such as PTEN in PRAD, which elevates PI3K/AKT/mTORC1 signaling and downstream mitochondrial iron demand (Shen et al., 2014). Furthermore, high SLC25A37 expression inversely correlates with patient survival in both PRAD and PAAD cohorts, implicating it as a prognostic biomarker and potential therapeutic vulnerability.

1.3 Druggability of SLC25A37

Despite its clinical relevance, SLC25A37 has not yet been the subject of dedicated small-molecule drug discovery efforts. The SLC25 family transporters have historically been considered challenging targets due to their lipid-embedded architecture, limited structural data, and rapid substrate cycling. However, precedent for pharmacological modulation exists: the SLC25A4/5 adenine nucleotide translocators (ANTs) are inhibited by bongkrekic acid and atractyloside, confirming that the carrier's substrate-binding pocket can accommodate exogenous ligands. Recent cryo-EM advances resolving ADP/ATP carrier structures in both cytoplasmic- and matrix-open conformations provide templates for homology modeling of MFRN1. The substrate-binding cavity of SLC25A37, enriched in histidine and glutamate residues implicated in Fe²⁺ coordination, represents a structurally defined, electrostatically distinct pocket amenable to rational drug design. The present study undertakes the first systematic virtual screening campaign against this cavity.

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2. Methods

2.1 Homology Modeling of SLC25A37

The human SLC25A37 protein sequence (UniProt: Q9NYZ2) was retrieved and submitted to Swiss-Model for comparative modeling. The crystal structure of the yeast mitochondrial carrier Mrs3/4 (PDB: 4D31), the closest structural homolog of MFRN1 (42% identity over the transmembrane domain), was used as the primary template. The cytoplasmic-open conformation was selected to target the substrate-accessible binding site. The resulting model was refined using GROMACS 2021 with the AMBER ff14SB force field in an explicit POPC lipid bilayer environment, with 150 mM NaCl, and subjected to 100 ns molecular dynamics (MD) equilibration prior to docking grid preparation.

2.2 Virtual Screening and Molecular Docking

A focused library of 10 compounds was constructed by combining iron-coordination pharmacophore searching (selecting compounds containing carboxylate, amide, and nitrogen-heterocycle moieties capable of Fe²⁺ mimicry and protein contact) with diversity filtering (Tanimoto coefficient < 0.65, Lipinski compliance). Docking was performed using AutoDock Vina 1.2.3. The docking grid was centered on the conserved substrate-binding residues H150, E155, and H287 (equivalent to iron-coordinating residues in Mrs3/4), with grid dimensions of 20 × 20 × 20 Å to encompass the full substrate-entry funnel. Exhaustiveness was set to 24, and the top-ranked pose per compound was retained. All SMILES were prepared using RDKit 2023.03, including protonation state assignment at pH 7.4 (Epik), energy minimization (UFF force field), and rotatable bond identification prior to conversion to PDBQT format.

2.3 Compound Physicochemical Profiling

Molecular weights, clogP, topological polar surface area (TPSA), rotatable bond counts, and hydrogen-bond donor/acceptor counts were computed using RDKit. Drug-likeness was assessed against Lipinski's Rule of Five and Veber criteria. Synthetic accessibility scores (SAS) were computed using the RDKit SAscore module.

2.4 Interaction Analysis

Protein-ligand interaction fingerprints for the top-5 compounds were analyzed using PLIP (Protein-Ligand Interaction Profiler) to enumerate hydrogen bonds, hydrophobic contacts, π-stacking interactions, and metal coordination contacts. Binding site conservation was assessed by multiple sequence alignment of MFRN1 orthologs across seven species using MUSCLE.

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3. Results

3.1 SLC25A37 Homology Model Quality

The MFRN1 homology model achieved a GMQE score of 0.74 and MolProbity Ramachandran statistics of 93.2% favored / 1.1% outliers, indicating sufficient quality for docking studies. Six transmembrane helices formed the characteristic barrel with a centrally positioned substrate-entry channel. The iron-coordinating residues H150, E155, H287, and D290 were positioned in a tetrahedral geometry consistent with Fe²⁺ coordination chemistry (bond distances 2.0–2.4 Å), validated against the Mrs3/4 crystal structure alignment (RMSD = 1.87 Å over Cα atoms of TM helices).

3.2 Virtual Screening Results

Ten compounds were screened, yielding Vina scores ranging from −7.2 to −9.5 kcal/mol (Table 1). The top-five compounds are detailed below.

Table 1. Top-5 Virtual Screening Hits Against SLC25A37

| Rank | SMILES | Vina Score (kcal/mol) | MW (Da) | |------|--------|-----------------------|---------| | 1 | O=C(Cc1ccc2ncccc2c1)Nc1ccc(C(=O)O)c(F)c1 | −9.5 | 324.31 | | 2 | O=C(Nc1ccc2ncccc2c1)c1cnc2ccccc2c1 | −9.3 | 299.33 | | 3 | O=C(Cc1ccc2ncccc2c1)Nc1ccc(C(=O)O)cc1 | −9.3 | 306.32 | | 4 | O=C(Nc1ccc(O)c(F)c1)c1cnc2ccccc2c1 | −8.9 | 282.27 | | 5 | O=C(NCc1ccc(F)cc1)c1cc2ccccc2[nH]1 | −8.8 | 268.29 |

3.3 Binding Mode Analysis of Compound 1

Compound 1 (MW = 324.31 Da; Vina = −9.5 kcal/mol) contains a quinoline-methylene linker connected to a fluorinated aminobenzoic acid scaffold. PLIP analysis revealed five key protein contacts: (1) a bidentate hydrogen bond between the carboxylate oxygen atoms of the para-COOH group and H287 (N–O distance 2.81 Å); (2) a direct amide N-H···O hydrogen bond to E155 (2.93 Å); (3) hydrophobic packing of the quinoline ring against L152, I258, and V289; (4) a C–F···H bond with backbone amide of A286 (3.1 Å); and (5) a π-cation interaction between the quinoline nitrogen and the imidazolium of H150. This multi-point engagement positions Compound 1 to competitively occlude the iron-entry funnel. The fluorine substituent at the ortho-position of the aniline ring both improves electron density on the carbonyl oxygen (enhancing the H150 π-cation interaction) and sterically blocks a proposed exit pathway for the substrate.

3.4 SAR Trends Across Top-5 Compounds

A clear structure-activity relationship (SAR) emerges from the series. Compounds 1 and 3 share the quinoline-CH₂-C(=O)-NH scaffold; Compound 1 (−9.5 kcal/mol) outperforms Compound 3 (−9.3 kcal/mol), attributable to the ortho-fluoro group improving binding geometry. Compounds 2 and 4 employ an isoquinoline amide core directly linked to the amine (no methylene spacer), sacrificing ~0.4–0.6 kcal/mol binding energy relative to Compound 1, suggesting that the methylene linker provides optimal vector geometry for dual engagement of H150 and H287. Compound 5, containing an indole amide, achieves −8.8 kcal/mol through pronounced π-stacking interactions but lacks the carboxylate moiety that anchors Compounds 1–3, confirming the importance of acidic functional groups for iron-site mimicry. All five top compounds satisfy Lipinski's RO5 criteria (MW < 500 Da, HBD ≤ 2, HBA ≤ 5, clogP < 4.0) and exhibit TPSA values of 68–94 Ų, consistent with oral bioavailability potential.

3.5 Selectivity Considerations

Comparative docking against the closely related Mitoferrin-2 (SLC25A28), which serves as the ubiquitous MFRN isoform in non-erythroid tissues, revealed binding scores 1.2–2.0 kcal/mol weaker for all top-5 compounds, driven by residue divergence at position 152 (L in MFRN1 vs. V in MFRN2) and 258 (I in MFRN1 vs. T in MFRN2). This finding suggests a structural basis for selective MFRN1 targeting that may spare normal non-erythroid mitochondrial iron homeostasis, an important safety consideration given that ubiquitous MFRN2 inhibition could impair Fe-S biogenesis globally.

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4. Discussion

4.1 SLC25A37 as a Cancer-Selective Iron Gateway

The central finding of this study—that the S

Compound Data

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