Rim Malek

All Publications

• MUC1-targeting small peptide radiopharmaceuticals for breast cancer. EJNMMI radiopharmacy and chemistry Malek, R., Landry, M., Cheung, P., Beinat, C. 2026

  Abstract

  Mucin 1 (MUC1) is a transmembrane glycoprotein overexpressed and underglycosylated in numerous epithelial cancers, including breast cancer. Reduced glycosylation leads to the exposure of the variable number tandem repeat (VNTR) region. To the best of our knowledge, all peptides previously described in the literature target the same epitope sequence of the VNTR. Given the high prevalence of breast cancer and the limited treatment options for the aggressive subtype triple-negative breast cancer (TNBC), due to its lack of oestrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2), we sought to develop a small peptide radiopharmaceutical targeting MUC1 by exploring all 3 minimal epitope sequences of the VNTR: RPAPGS, PPAHGVT and PDTRP. We also investigated the influence of linker lipophilicity on the binding affinity to MUC1.The reference compound 1 showed the highest cell uptake among all tested compounds. While some statistically significant differences were observed for the cell uptake between the different peptide sequences and the linkers, the uptake was so low that no reliable structure-activity relationships could be established. We then studied the specificity of all compounds for MUC1 by comparing the uptake in MUC1-expressing and MUC1-knockout (KO) cells, and unexpectedly observed no specificity for any compound. A saturation binding assay of several peptides showed their binding was too low to reliably determine their binding affinity (Kd). Surface plasmon resonance (SPR) further confirmed the absence of binding of all [NatGa]- and [NatLu]-labelled peptides tested. Given the discrepancies between our cell data and the previously reported results, we next assessed the specificity of the reference (1) in vivo in mice bearing MUC1-expressing and MUC1-knockdown (KD) tumours, which further proved its non-specificity.While MUC1 is a very promising target for the development of breast cancer theranostics, designing peptidomimetics based on its minimal epitopes do not lead to high-affinity binders. Our ongoing efforts involve utilizing phage-display to identify new peptide sequences.

  View details for DOI 10.1186/s41181-026-00451-1

  View details for PubMedID 42068440

• <SUP>18</SUP>F-MGX-110S detects proinflammatory innate immune responses in human cells and Alzheimer's disease mice with high sensitivity Kalita, M., Kuo, R., Reyes, S., Straniero, V., Nagy, S., D'Moore, D., Sundar, M., Setiadi, A., Mak, S., Tuffley, G., Pandrala, M., Marsango, S., Alam, I., Inay, G., Lanzini, A., Malek, R., Brooks, A., Kaur, T., Beinat, C., Valoti, E., Milligan, G., Scott, P., James, M. ELSEVIER SCIENCE INC. 2025

  View details for DOI 10.1016/j.nucmedbio.2025.109375

  View details for Web of Science ID 001632350100030

• Participant metabolic state impacts glioma PET imaging: Translational insights from [18F]DASA-10 and FDG Abdi, S., Moses, A., Malek, R., Cheung, P., Landry, M., Recht, L., Beinat, C. OXFORD UNIV PRESS INC. 2025: v440

  View details for DOI 10.1093/neuonc/noaf201.1739

  View details for Web of Science ID 001613245000032

• Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer. Theranostics Moses, A., Malek, R., Kendirli, M. T., Cheung, P., Landry, M., Herrera-Barrera, M., Khojasteh, A., Granucci, M., Bukhari, S. A., Hooper, J. E., Hayden-Gephart, M., Dixon, S. J., Recht, L. D., Beinat, C. 2025; 15 (3): 836-849

  Abstract

  Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, characterized by resistance to conventional therapies and poor survival. Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has recently emerged as a promising therapeutic target for GBM treatment. However, there are currently no non-invasive imaging techniques to monitor the engagement of pro-ferroptotic compounds with their respective targets, or to monitor the efficacy of ferroptosis-based therapies. System xc-, an important player in cellular redox homeostasis, plays a critical role in ferroptosis by mediating the exchange of cystine for glutamate, thus regulating the availability of cysteine, a crucial precursor for glutathione synthesis, and influencing the cellular antioxidant defense system. We have recently reported the development and validation of [18F]hGTS13, a radiopharmaceutical specific for system xc-. Methods: In the current work, we characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [18F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing investigational compounds. We then associated changes in [18F]hGTS13 uptake with cellular glutathione content. Furthermore, we evaluated [18F]hGTS13 uptake in a rat model of glioma, both before and after treatment with imidazole ketone erastin (IKE), a pro-ferroptotic inhibitor of system xc- activity. Results: Treatment with erastin2, a system xc- inhibitor, significantly decreased [18F]hGTS13 uptake and cellular glutathione content in vitro. Dynamic PET/CT imaging of C6 glioma-bearing rats with [18F]hGTS13 revealed high and sustained uptake within the intracranial glioma and this uptake was decreased upon pre-treatment with IKE. Conclusion: In summary, [18F]hGTS13 represents a promising tool to distinguish cell types that demonstrate sensitivity or resistance to ferroptosis-inducing therapies that target system xc-, and monitor the engagement of these drugs.

  View details for DOI 10.7150/thno.101882

  View details for PubMedID 39776801

  View details for PubMedCentralID PMC11700874

• Synthesis and preclinical evaluation of [<SUP>18</SUP>F]DASA-10 a second generation PKM2 specific radiotracer Beinat, C., Malek, R., Kendrili, M., Acosta, C., Habte, F., Recht, L. ELSEVIER SCIENCE INC. 2023: S35

  View details for Web of Science ID 001128725600046

• PET imaging of focused-ultrasound enhanced delivery of AAVs into the murine brain. Theranostics Ajenjo, J., Seo, J. W., Foiret, J., Wu, B., Raie, M. N., Wang, J., Fite, B. Z., Zhang, N., Malek, R., Beinat, C., Malik, N., Anders, D. A., Ferrara, K. W. 2023; 13 (15): 5151-5169

  Abstract

  Rationale: Despite recent advances in the use of adeno-associated viruses (AAVs) as potential vehicles for genetic intervention of central and peripheral nervous system-associated disorders, gene therapy for the treatment of neuropathology in adults has not been approved to date. The currently FDA-approved AAV-vector based gene therapies rely on naturally occurring serotypes, such as AAV2 or AAV9, which display limited or no transport across the blood-brain barrier (BBB) if systemically administered. Recently developed engineered AAV variants have shown broad brain transduction and reduced off-target liver toxicity in non-human primates (NHPs). However, these vectors lack spatial selectivity for targeted gene delivery, a potentially critical limitation for delivering therapeutic doses in defined areas of the brain. The use of microbubbles, in conjunction with focused ultrasound (FUS), can enhance regional brain AAV transduction, but methods to assess transduction in vivo are needed. Methods: In a murine model, we combined positron emission tomography (PET) and optical imaging of reporter gene payloads to non-invasively assess the spatial distribution and transduction efficiency of systemically administered AAV9 after FUS and microbubble treatment. Capsid and reporter probe accumulation are reported as percent injected dose per cubic centimeter (%ID/cc) for in vivo PET quantification, whereas results for ex vivo assays are reported as percent injected dose per gram (%ID/g). Results: In a study spanning accumulation and transduction, mean AAV9 accumulation within the brain was 0.29 %ID/cc without FUS, whereas in the insonified region of interest of FUS-treated mice, the spatial mean and maximum reached ~2.3 %ID/cc and 4.3 %ID/cc, respectively. Transgene expression assessed in vivo by PET reporter gene imaging employing the pyruvate kinase M2 (PKM2)/[18F]DASA-10 reporter system increased up to 10-fold in the FUS-treated regions, as compared to mice receiving AAVs without FUS. Systemic injection of AAV9 packaging the EF1A-PKM2 transgene followed by FUS in one hemisphere resulted in 1) an average 102-fold increase in PKM2 mRNA concentration compared to mice treated with AAVs only and 2) a 12.5-fold increase in the insonified compared to the contralateral hemisphere of FUS-treated mice. Conclusion: Combining microbubbles with US-guided treatment facilitated a multi-hour BBB disruption and stable AAV transduction in targeted areas of the murine brain. This unique platform has the potential to provide insight and aid in the translation of AAV-based therapies for the treatment of neuropathologies.

  View details for DOI 10.7150/thno.85549

  View details for PubMedID 37908737

  View details for PubMedCentralID PMC10614693

• Development of [18F]DASA-10 for enhanced imaging of pyruvate kinase M2. Nuclear medicine and biology Kendirli, M. T., Malek, R., Silveira, M. B., Acosta, C., Zhang, S., Azevedo, C., Nagy, S. C., Habte, F., James, M. L., Recht, L. D., Beinat, C. 2023; 124-125: 108382

  Abstract

  The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [18F]DASA-23.First, we synthesized [18F]DASA-10 and tested its uptake and retention compared to [18F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [18F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [18F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [18F]DASA-10 versus [18F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma.[18F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [18F]DASA-23 in all cell lines and timepoints investigated. [18F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [18F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [18F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01).[18F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [18F]DASA-23. [18F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.

  View details for DOI 10.1016/j.nucmedbio.2023.108382

  View details for PubMedID 37634399

• Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation MOLECULES Malek, R., Simakov, A., Davis, A., Maj, M., Bernard, P. J., Wnorowski, A., Martin, H., Marco-Contelles, J., Chabchoub, F., Dallemagne, P., Rochais, C., Jozwiak, K., Ismaili, L. 2023; 28 (1)

  Abstract

  Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

  View details for DOI 10.3390/molecules28010071

  View details for Web of Science ID 000910211400001

  View details for PubMedID 36615267

  View details for PubMedCentralID PMC9822022

• New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H-3 Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition JOURNAL OF MEDICINAL CHEMISTRY Malek, R., Arribas, R. L., Palomino-Antolin, A., Totoson, P., Demougeot, C., Kobrlova, T., Soukup, O., Iriepa, I., Moraleda, I., Diez-Iriepa, D., Godyn, J., Panek, D., Malawska, B., Gluch-Lutwin, M., Mordyl, B., Siwek, A., Chabchoub, F., Marco-Contelles, J., Kiec-Kononowicz, K., Egea, J., de los Rios, C., Ismaili, L. 2019; 62 (24): 11416-11422

  Abstract

  New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.

  View details for DOI 10.1021/acs.jmedchem.9b00937

  View details for Web of Science ID 000505633400029

  View details for PubMedID 31724859

• Multi-target 1,4-dihydropyridines showing calcium channel blockade and antioxidant capacity for Alzheimer's disease therapy BIOORGANIC CHEMISTRY Malek, R., Maj, M., Wnorowski, A., Jozwiak, K., Martin, H., Iriepa, I., Moraleda, I., Chabchoub, F., Marco-Contelles, J., Ismaili, L. 2019; 91: 103205

  Abstract

  In this work we describe the synthesis, Ca+2 channel blockade capacity and antioxidant power of N3,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxamides 1-9, a number of multi-target small 1,4-dihydropyridines (DHP), designed by juxtaposition of melatonin and nimodipine. As a result, we have identified antioxidant DHP 7 (Ca2+ channel blockade: 55%, and 8.78 Trolox/Equivalents), the most balanced DHP analyzed here, for potential Alzheimer's disease therapy.

  View details for DOI 10.1016/j.bioorg.2019.103205

  View details for Web of Science ID 000487812000076

  View details for PubMedID 31446330

• Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY Dgachi, Y., Martin, H., Malek, R., Jun, D., Janockova, J., Sepsova, V., Soukup, O., Iriepa, I., Moraleda, I., Maalej, E., Carmo Carreiras, M., Refouvelet, B., Chabchoub, F., Marco-Contelles, J., Ismaili, L. 2019; 34 (1): 163-170

  Abstract

  In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aβ1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.

  View details for DOI 10.1080/14756366.2018.1538136

  View details for Web of Science ID 000451541800001

  View details for PubMedID 30482062

  View details for PubMedCentralID PMC6263107

• Synthesis and Biological Evaluation of Novel Chromone plus Donepezil Hybrids for Alzheimer's Disease Therapy CURRENT ALZHEIMER RESEARCH Malek, R., Refouvelet, B., Benchelcroun, M., Iriepa, I., Moraleda, I., Andrys, R., Musilek, K., Marco-Contelles, J., Ismaili, L. 2019; 16 (9): 815-820

  Abstract

  Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets.We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals.We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed.Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development.The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.

  View details for DOI 10.2174/1567205016666191011112624

  View details for Web of Science ID 000493721100004

  View details for PubMedID 31660831