RESUMO
INTRODUCTION: Nearly two decades after leucine rich repeat kinase 2 (LRRK2) was discovered as a genetic determinant of Parkinson's disease (PD), LRRK2 has emerged a priority therapeutic target in PD and inhibition of its activity is hypothesized to be beneficial. AREAS COVERED: LRRK2 targeting agents, in particular kinase inhibitors and agents reducing LRRK2 expression show promise in model systems and have progressed to phase I and phase II clinical testing for PD. Several additional targeting strategies for LRRK2 are emerging, based on promoting specific 'healthy' LRRK2 quaternary structures, heteromeric complexes and conformations. EXPERT OPINION: It can be expected that LRRK2 targeting strategies may proceed to phase III clinical testing for PD in the next five years, allowing the field to discover the real clinical value of LRRK2 targeting strategies.
Assuntos
Antiparkinsonianos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Patentes como Assunto , Inibidores de Proteínas Quinases , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Animais , Inibidores de Proteínas Quinases/farmacologia , Antiparkinsonianos/farmacologia , Terapia de Alvo Molecular , Desenvolvimento de MedicamentosRESUMO
In the search for new small molecules for the therapy of neuropathic pain, we found that 2-{3-[N-(1-benzylpiperidin-4-yl)propyl]amino}-6-[N-methyl-N-(prop-2-yn-1-yl)amino]-4-phenylpyridine-3,5-dicarbonitrile (12) induced a robust antiallodynic effect in capsaicin-induced mechanical allodynia, a behavioural model of central sensitization, through σ1R antagonism. Furthermore, administration of compound 12 to neuropathic animals, fully reversed mechanical allodynia, increasing its mechanical threshold to levels that were not significantly different from those found in paclitaxel-vehicle treated mice or from basal levels before neuropathy was induced. Ligand 12 is thus a promising hit-compound for the therapy of neuropathic pain.
Assuntos
Neuralgia , Nitrilas , Animais , Neuralgia/tratamento farmacológico , Camundongos , Masculino , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Analgésicos/farmacologia , Analgésicos/química , Analgésicos/síntese química , Analgésicos/uso terapêutico , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Piridinas/uso terapêutico , Receptor Sigma-1 , Capsaicina/farmacologia , Capsaicina/química , Hiperalgesia/tratamento farmacológico , Hiperalgesia/induzido quimicamenteRESUMO
The epidermal growth factor receptor (EGFR) family is a class of transmembrane proteins, highly regarded as anticancer targets due to their pivotal role in various malignancies. Standard cancer treatments targeting the ErbB receptors include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Despite their substantial survival benefits, the achievement of curative outcomes is hindered by acquired resistance. Recent advancements in anti-ErbB approaches, such as inhibitory peptides, nanobodies, targeted-protein degradation strategies, and bispecific antibodies (BsAbs), aim to overcome such resistance. More recently, emerging insights into the cell surface interactome of the ErbB family open new avenues for modulating ErbB signaling by targeting specific domains of ErbB partners. Here, we review recent progress in ErbB targeting and elucidate emerging paradigms that underscore the significance of EGF domain-containing proteins (EDCPs) as new ErbB-targeting pathways.
Assuntos
Receptores ErbB , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/imunologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacosRESUMO
Melatonin is a small natural compound, so called a neuro-hormone that is synthesized mainly in pineal gland in animals. Its main role is to master the clock of the body, under the surveillance of light. In other words, it transfers the information concerning night and day to the peripheral organs which, without it, could not "know" which part of the circadian rhythm the body is in. Besides its main circadian and circannual rhythms mastering, melatonin is reported to be a radical scavenger and/or an antioxidant. Because radical scavengers are chemical species able to neutralize highly reactive and toxic species such as reactive oxygen species, one would like to transfer this property to living system, despite impossibilities already largely reported in the literature. In the present commentary, we refresh the memory of the readers with this notion of radical scavenger, and review the possible evidence that melatonin could be an in vivo radical scavenger, while we only marginally discuss here the fact that melatonin is a molecular antioxidant, a feature that merits a review on its own. We conclude four things: (i) the evidence that melatonin is a scavenger in acellular systems is overwhelming and could not be doubted; (ii) the transposition of this property in living (animal) systems is (a) theoretically impossible and (b) not proven in any system reported in the literature where most of the time, the delay of the action of melatonin is over several hours, thus signing a probable induction of cellular enzymatic antioxidant defenses; (iii) this last fact needs a confirmation through the discovery of a nuclear factor-a key relay in induction processes-that binds melatonin and is activated by it and (iv) we also gather the very important description of the radical scavenging capacity of melatonin in acellular systems that is now proven and shared by many other double bond-bearing molecules. We finally discussed briefly on the reason-scientific or else-that led this description, and the consequences of this claim, in research, in physiology, in pathology, but most disturbingly in therapeutics where a vast amount of money, hope, and patient bien-être are at stake.
Assuntos
Melatonina , Glândula Pineal , Animais , Humanos , Melatonina/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glândula Pineal/metabolismo , Ritmo Circadiano/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Protein-drug interactions are crucial for understanding drug delivery and cell functions. Jacalin is a suitable molecule for such targeting, as it specifically recognizes the tumor-associated Thomsen-Friedenreich (TF) antigen that is expressed on the glycosylated proteins in cancer cells. The present paper describes the interaction of curcumin and jacalin, a possible carrier molecule for the delivery of antitumor drugs due to its ability to recognize tumor cells. Our results have shown that both steady-state fluorescence and fluorescent labelling of jacalin are two reliable methods to determine jacalin-curcumin interactions. The affinity of jacalin for curcumin is consistently within the micromolar range (using fluorescence and microscale thermophoresis) showing high-affinity binding of the complex. In vitro experiments on triple-negative breast cancer MDA-MB-231 cells indicated inhibition of cell growth after treating with the jacalin-curcumin complex for 48 h. The cell survival fraction was significantly reduced to 50% after combined treatment. In this paper, we report for the first time about the jacalin-curcumin interaction. We quantified this unique biomolecular interaction and gathered additional information on the binding event. We observed that the jacalin-curcumin complex inhibits the proliferation of the triple-negative breast cancer MDA-MB-231 cells.
Assuntos
Antineoplásicos , Neoplasias da Mama , Curcumina , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Curcumina/química , Neoplasias da Mama/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Células MDA-MB-231 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células , Antígenos de Neoplasias/farmacologia , Linhagem Celular Tumoral , ApoptoseRESUMO
The past fifty years have been marked by the surge of neurodegenerative diseases. Unfortunately, current treatments are only symptomatic. Hence, the search for new and innovative therapeutic targets for curative treatments becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AAR) has been the subject of much research in recent years. In this paper, we report the design, synthesis and pharmacological analysis of quinazoline derivatives as A2AAR antagonists with high ligand efficiency. This class of molecules has been discovered by a virtual screening and bears no structural semblance with reference antagonist ZM-241385. More precisely, we identified a series of 2-aminoquinazoline as promising A2AAR antagonists. Among them, one compound showed a high affinity towards A2AAR (21a, Ki = 20 nM). We crystallized this ligand in complex with A2AAR, confirming one of our predicted docking poses and opening up possibilities for further optimization to derive selective ligands for specific adenosine receptor subtypes.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antagonistas de Receptores Purinérgicos P1 , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Antagonistas de Receptores Purinérgicos P1/farmacologia , Quinazolinas/farmacologia , Receptor A2A de Adenosina/química , Relação Estrutura-AtividadeRESUMO
The Hippo signaling pathway plays a fundamental role in the control of organ growth, cell proliferation, and stem cell characters. TEADs are the main transcriptional output regulators of the Hippo signaling pathway and bind to YAP and TAZ co-activators. TEAD1-4 are expressed differently, depending on the tissue and developmental level, and can be overexpressed in certain pathologies. TEAD ligands mainly target the internal pocket of the C-terminal domain of TEAD, and the first ligands selective for TEAD1 and TEAD3 have been recently reported. In this paper, we focus on the topographic homology of the TEAD C-terminal domain both externally and in the internal pocket to highlight the possibility of rationally designing ligands selective for one of the TEAD family members. We identified a novel TEAD2-specific pocket and reported its first ligand. Finally, AlphaFold2 models of full-length TEADs suggest TEAD autoregulation and emphasize the importance of the interface 2.
Assuntos
Via de Sinalização Hippo , Fatores de Transcrição , Proliferação de Células , Ligantes , Fatores de Transcrição/metabolismoRESUMO
The Leucine Rich Repeat Kinase 2 (LRRK2) gene is a major genetic determinant of Parkinson's disease (PD), encoding a homonymous multi-domain protein with two catalytic activities, GTPase and Kinase, involved in intracellular signaling and trafficking. LRRK2 is phosphorylated at multiple sites, including a cluster of autophosphorylation sites in the GTPase domain and a cluster of heterologous phosphorylation sites at residues 860 to 976. Phosphorylation at these latter sites is found to be modified in brains of PD patients, as well as for some disease mutant forms of LRRK2. The main aim of this study is to investigate the functional consequences of LRRK2 phosphorylation or dephosphorylation at LRRK2's heterologous phosphorylation sites. To this end, we generated LRRK2 phosphorylation site mutants and studied how these affected LRRK2 catalytic activity, neurite outgrowth and lysosomal physiology in cellular models. We show that phosphorylation of RAB8a and RAB10 substrates are reduced with phosphomimicking forms of LRRK2, while RAB29 induced activation of LRRK2 kinase activity is enhanced for phosphodead forms of LRRK2. Considering the hypothesis that PD pathology is associated to increased LRRK2 kinase activity, our results suggest that for its heterologous phosphorylation sites LRRK2 phosphorylation correlates to healthy phenotypes and LRRK2 dephosphorylation correlates to phenotypes associated to the PD pathological processes.
Assuntos
Doença de Parkinson , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lisossomos/metabolismo , Doença de Parkinson/metabolismo , Fosforilação/fisiologia , Transdução de SinaisRESUMO
Lactate dehydrogenases (LDHs) are tetrameric enzymes of therapeutic relevance for cancer therapy due to their important implications in cancer cell metabolism. LDH active site inhibition suffers from different drawbacks due to several features such as high cellular concentration and a shared active site among the dehydrogenase family. Conversely, targeting the LDH oligomeric state is an exciting strategy that could provide a suitable alternative to active-site inhibition. In the present study, we developed a biophysical screening cascade to probe the LDHs tetrameric interface. Using nanoscale differential fluorimetry (nanoDSF) as a primary screening method, we identified a series of hits that destabilize the tetrameric protein. From this primary screening, we validated selected hits using saturation transfer difference nuclear magnetic resonance (STD NMR) and microscale thermophoresis (MST) as a combination of orthogonal biophysical techniques. Finally, we characterized the validated hits and demonstrated that they specifically interact at the tetrameric interface of LDH-1 and LDH-5 and can inhibit the LDH tetramerization process. Overall, this work provides a convenient method for screening ligands at the LDH tetrameric interface and has identified promising hits suitable for further optimization. We believe that this biophysical screening cascade, especially the use of (nano)DSF, could be extended to other homomeric proteins.
Assuntos
Lactato Desidrogenases , Fluorometria , Lactato Desidrogenases/antagonistas & inibidores , Ligantes , Espectroscopia de Ressonância MagnéticaRESUMO
In our constant search for new successors of agomelatine, we report herein a new series of compounds resulting from bioisosteric modulation of the naphthalene ring. The isoquinoline and tetrahydroisoquinoline derivatives were synthesized and pharmacologically evaluated. This isosteric replacement of the naphthalene group of agomelatine has led to potent agonist and partial agonist compounds with nanomolar melatonergic binding affinities. Overall, the presence of a nitrogen atom was accompanied with a decrease in the binding affinity toward both MT1 and MT2 and the loss of 5HT2C response, especially for tetrahydroisoquinoline in comparison with the parent compound. Interestingly, due to the presence of this nitrogen atom, a notable improvement in the pharmacokinetic properties was observed for all compounds.
Assuntos
Isoquinolinas/farmacologia , Receptores de Melatonina/agonistas , Animais , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Selenium is an underexplored element that can be used for bioisosteric replacement of lower molecular weight chalcogens such as oxygen and sulfur. More studies regarding the impact of selenium substitution in different chemical scaffolds are needed to fully grasp this element's potential. Herein, we decided to evaluate the impact of selenium incorporation in a series of tryptophan 2,3-dioxygenase (TDO2) inhibitors, a target of interest in cancer immunotherapy. First, we synthesized the different chalcogen isosteres through Suzuki-Miyaura type coupling. Next, we evaluated the isosteres' affinity and selectivity for TDO2, as well as their lipophilicity, microsomal stability and cellular toxicity on TDO2-expressing cell lines. Overall, chalcogen isosteric replacements did not disturb the on-target activity but allowed for a modulation of the compounds' lipophilicity, toxicity and stability profiles. The present work contributes to our understanding of oxygen/sulfur/selenium isostery towards increasing structural options in medicinal chemistry for the development of novel and distinctive drug candidates.
Assuntos
Calcogênios/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Selênio/farmacologia , Triptofano Oxigenase/antagonistas & inibidores , Calcogênios/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Oxigênio/química , Oxigênio/farmacologia , Selênio/química , Estereoisomerismo , Relação Estrutura-Atividade , Enxofre/química , Enxofre/farmacologia , Triptofano Oxigenase/metabolismoRESUMO
The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at the molecular level the role and impact of the MUC4EGF domains in the mediation of the binding affinities with HER2 and the PC cell tumorigenicity. We used an integrative approach combining in vitro bioinformatic, biophysical, biochemical, and biological approaches, as well as an in vivo study on a xenograft model of PC. In this study, we specified the binding mode of MUC4EGF domains with HER2 and demonstrate their "growth factor-like" biological activities in PC cells leading to stimulation of several signaling proteins (mTOR pathway, Akt, and ß-catenin) contributing to PC progression. Molecular dynamics simulations of the MUC4EGF/HER2 complexes led to 3D homology models and identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results will pave the way to the design of potential MUC4/HER2 inhibitors targeting the EGF domains of MUC4. This strategy will represent a new efficient alternative to treat cancers associated with MUC4/HER2 overexpression and HER2-targeted therapy failure as a new adapted treatment to patients.
RESUMO
The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Descoberta de Drogas , Pirazóis/farmacologia , Fatores de Transcrição de Domínio TEA/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Fatores de Transcrição de Domínio TEA/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismoRESUMO
Tryptophan 2,3-dioxygenase (TDO2) is a heme-containing enzyme constitutively expressed at high concentrations in the liver and responsible for l-tryptophan (l-Trp) homeostasis. Expression of TDO2 in cancer cells results in the inhibition of immune-mediated tumor rejection due to an enhancement of l-Trp catabolism via the kynurenine pathway. In the study herein, we disclose a new 6-(1H-indol-3-yl)-benzotriazole scaffold of TDO2 inhibitors developed through rational design, starting from existing inhibitors. Rigidification of the initial scaffold led to the synthesis of stable compounds displaying a nanomolar cellular potency and a better understanding of the structural modulations that can be accommodated inside the active site of hTDO2.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Triazóis/farmacologia , Triptofano Oxigenase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triptofano Oxigenase/metabolismo , Células Tumorais CultivadasRESUMO
Protein self-association is a universal phenomenon essential for stability and molecular recognition. Disrupting constitutive homomers constitutes an original and emerging strategy in drug design. Inhibition of homomeric proteins can be achieved through direct complex disruption, subunit intercalation, or by promoting inactive oligomeric states. Targeting self-interaction grants several advantages over active site inhibition because of the stimulation of protein degradation, the enhancement of selectivity, substoichiometric inhibition, and by-pass of compensatory mechanisms. This new landscape in protein inhibition is driven by the development of biophysical and biochemical tools suited for the study of homomeric proteins, such as differential scanning fluorimetry (DSF), native mass spectrometry (MS), Förster resonance energy transfer (FRET) spectroscopy, 2D nuclear magnetic resonance (NMR), and X-ray crystallography. In this review, we discuss the different aspects of this new paradigm in drug design.
Assuntos
Desenho de Fármacos , Terapia de Alvo Molecular , Proteínas/metabolismo , Domínio Catalítico , Humanos , Ligação Proteica , Proteínas/antagonistas & inibidoresRESUMO
Despite being initially regarded as a metabolic waste product, lactate is now considered to serve as a primary fuel for the tricarboxylic acid cycle in cancer cells. At the core of lactate metabolism, lactate dehydrogenases (LDHs) catalyze the interconversion of lactate to pyruvate and as such represent promising targets in cancer therapy. However, direct inhibition of the LDH active site is challenging from physicochemical and selectivity standpoints. However, LDHs are obligate tetramers. Thus, targeting the LDH tetrameric interface has emerged as an appealing strategy. In this work, we examine a dimeric construct of truncated human LDH to search for new druggable sites. We report the identification and characterization of a new cluster of interactions in the LDH tetrameric interface. Using nanoscale differential scanning fluorimetry, chemical denaturation, and mass photometry, we identified several residues (E62, D65, L71, and F72) essential for LDH tetrameric stability. Moreover, we report a family of peptide ligands based on this cluster of interactions. We next demonstrated these ligands to destabilize tetrameric LDHs through binding to this new tetrameric interface using nanoscale differential scanning fluorimetry, NMR water-ligand observed via gradient spectroscopy, and microscale thermophoresis. Altogether, this work provides new insights on the LDH tetrameric interface as well as valuable pharmacological tools for the development of LDH tetramer disruptors.
Assuntos
Mapeamento de Epitopos/métodos , L-Lactato Desidrogenase/metabolismo , Humanos , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/fisiologia , Lactato Desidrogenases/metabolismo , Ácido Láctico/metabolismo , Ligantes , Imageamento por Ressonância Magnética/métodos , Peptídeos/metabolismoRESUMO
Lactate dehydrogenases (LDHs) are tetrameric enzymes of major significance in cancer metabolism as well as promising targets for cancer therapy. However, their wide and polar catalytic sites make them a challenging target for orthosteric inhibition. In this work, we conceived to target LDH tetramerization sites with the ambition of disrupting their oligomeric state. To do so, we designed a protein model of a dimeric LDH-H. We exploited this model through WaterLOGSY nuclear magnetic resonance and microscale thermophoresis for the identification and characterization of a set of α-helical peptides and stapled derivatives that specifically targeted the LDH tetramerization sites. This strategy resulted in the design of a macrocyclic peptide that competes with the LDH tetramerization domain, thus disrupting and destabilizing LDH tetramers. These peptides and macrocycles, along with the dimeric model of LDH-H, constitute promising pharmacological tools for the de novo design and identification of LDH tetramerization disruptors. Overall, our study demonstrates that disrupting LDH oligomerization state by targeting their tetramerization sites is achievable and paves the way toward LDH inhibition through this novel molecular mechanism.
Assuntos
Antineoplásicos/metabolismo , L-Lactato Desidrogenase/metabolismo , Peptídeos Cíclicos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Sítio Alostérico , Sequência de Aminoácidos , Antineoplásicos/química , Humanos , L-Lactato Desidrogenase/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein-protein interactions, with receptor tyrosine kinase ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome, thus raising interest in therapeutic targeting. This paper aims to demonstrate that MUC3, MUC4, MUC12, MUC13, and MUC17 have a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure-function relationship analysis of the conserved domains indicated that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes is discussed, revealing ErbB2-related pathways of cell signaling to be targeted.