Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor

Rebolledo-Bustillo, Mariana; Garcia-Gomez, David; Dávila, Eliud Morales; Castro, María Eugenia; Caballero, Norma A.; Meléndez, Francisco J.; Baizabal-Aguirre, Víctor M.; Sánchez-Gaytán, Brenda L.; Pérez-Aguilar, José Manuel

doi:10.3390/ijms24054393

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Clinical studies are ongoing for the mobilization of CD34+ HSCs for gene therapy in patients with sickle cell disease [ 34 , 36 ]. In phase I, motixafortide was able to rapidly mobilize CD34+ cells and immune cells in healthy volunteers [ 37 , 38 , 39 ]. Motixafortide also showed promising data in pancreatic, breast, and lung cancers [ 40 ].…”

Section: Peptidesmentioning

confidence: 99%

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

Al Shaer,

Al Musaimi,

Albericio

et al. 2024

Pharmaceuticals

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A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects.

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Section: Peptidesmentioning

confidence: 99%

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

Al Shaer,

Al Musaimi,

Albericio

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Motixafortide (BL-8040, BKT-140, TNI4001) is a synthetic peptide CXCR4 inhibitor being tested in both solid and liquid cancers. Motixafortide binds the same pocket on CXCR4 as its ligand CXCL12/SDF-1, thereby stabilizing the inactive conformations of CXCR4, preventing its activation [228]. Since Motixafortide acts as an inverse agonist, occupying the binding pocket of CXCR4 without stimulating the receptor, it prevents the rehoming of leukemic blasts to the bone marrow.…”

Section: Peptidesmentioning

confidence: 99%

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

MacLean,

Walker,

Arun

et al. 2024

IJMS

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Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.

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“…Given the challenges of predicting the oncogenic status of GPCR mutations, many authors have opted to study the structural impact of cancer-related mutations on the receptor's stability and activation mechanism. This can be useful to pinpoint novel potential biomarkers, such as the olfactory receptor OR2T7 destabilizing mutation D125V in glioblastoma [97], or to gain further insights into the activating and binding mechanisms of established anticancer targets, such as CXCR4 [98] or SMO [99], to improve the development of targeted therapies.…”

Section: G Protein-coupled Receptorsmentioning

confidence: 99%

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities

Gorostiola González,

Rakers,

Jespers

et al. 2024

IJMS

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Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of “wet-lab” experiments. In this review, we explore the applications of computational approaches in membrane protein oncological characterization, particularly focusing on three prominent membrane protein families: receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and solute carrier proteins (SLCs). We chose these families due to their varying levels of understanding and research data availability, which leads to distinct challenges and opportunities for computational analysis. We discuss the utilization of multi-omics data, machine learning, and structure-based methods to investigate aberrant protein functionalities associated with cancer progression within each family. Moreover, we highlight the importance of considering the broader cellular context and, in particular, cross-talk between proteins. Despite existing challenges, computational tools hold promise in dissecting membrane protein dysregulation in cancer. With advancing computational capabilities and data resources, these tools are poised to play a pivotal role in identifying and prioritizing membrane proteins as personalized anticancer targets.

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Structural Basis of the Binding Mode of the Antineoplastic Compound Motixafortide (BL-8040) in the CXCR4 Chemokine Receptor

Cited by 8 publications

References 34 publications

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

2023 FDA TIDES (Peptides and Oligonucleotides) Harvest

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities

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