LY2510924 / Eli Lilly - LARVOL DELTA

Development and in vitro/in vivo evaluation of taste-masked orodispersible films of dapoxetine hydrochloride using ion exchange resins. (PubMed, Drug Deliv Transl Res) - "It was found that the based-Kyron T-134 resin complex achieved a high drug loading of 75.9 ± 1.4%, establishing the mass ratio of dapoxetine hydrochloride to Kyron T-134 at 2:1, and adjusting the solution pH to 5.4 ± 0.05. Furthermore, pharmacokinetic studies conducted in healthy volunteers demonstrated that the ODFs were bioequivalent to Priligy®. Therefore, this ODFs, characterized by its pleasant taste and water-free administration, offer a novel and convenient oral formulation for patients with PE, thereby enhancing patient compliance."

Journal • Preclinical • Sexual Disorders

Combined CXCR-4 Inhibition with Novel Agent GPC-100 (burixafor) and Beta 2 Adrenergic Receptor Blockade Enhances Cytarabine Response for Acute Myeloid Leukemia Blasts on Stroma (ASH 2024) - P1 | "The CXCR4 inhibitor plerixafor improves yields of mobilized normal hematopoietic stem cells (HSCs) in combination with filgrastim (G-CSF). Clinical trials of CXCR4 inhibitors have been conducted to mobilize AML out of the protected BM niche, including plerixafor with 7+3 or MEC, BL-8040 with cytarabine (araC), LY2510924 with idarubicin/araC, and ulocuplumab (human IgG4 antibody) with MEC...In addition, high throughput drug screening of AML on stroma, but not in suspension or on CXCL12 coated plates, revealed that combination of the CXCR4 inhibitor GPC-100 and beta blocker propranolol, with araC, increased drug sensitivity (reduced IC50 by ≥4 to >10 fold) as compared to araC alone for AML cells on HS-5 human stromal cell line or autologous patient mesenchymal stromal cells...Conclusions : These studies support further investigation of whether simultaneous blockade of CXCR4 and ADRB2 may potentiate chemotherapy response in AML, perhaps by disrupting..."

Stroma • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ADRB2 • CD58 • CXCL12 • CXCR4 • FLT3 • NPM1 • TP53

Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924. (PubMed, Eur J Nucl Med Mol Imaging) - "[18F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an 18F-alternative to [68Ga]PentixaFor."

Journal • Hematological Malignancies • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • CD4 • CXCR4

Real-Life Benefit-Risk Assessment of Medical Products Using Bayesian Multi-Criteria Augmented Decision Analysis (MCADA) in Oncology (ISPOR-EU 2024) - P2 | " In the first case study on small-cell lunger cancer , we found the treatment (LY2510924) added to standard-of-care (carboplatin + etoposide) had lower utility compared to the standard-of-care alone under the linear and non-linear utility assumptions...The second case study on metastatic pancreatic cancer showed lower utility for experimental treatment (CO-1.01) compared to the standard-of-care ( gemcitabine; mean : -0.06; 95%CrI: -0.15, 0.04)... In our case studies, MCADA was able to point to lack of clinical benefit in experimental therapies more clearly . MCADA can be used as a supplemental analys i s to facilitate go/no-go decisions i n early clinical development programs for oncology. MCADA can accommodate variables in their natural forms without imposing linear utility assumptions and be used to as an optimal tool for clinical development."

Clinical • Hepatology • Lung Cancer • Oncology • Pancreatic Cancer • Small Cell Lung Cancer • Solid Tumor

Selective PET imaging using the Al18F-labeled CXCR4 antagonist LY2510924: "Al18F-NOTA-SC, the new kid on the block". (EANM 2024) - "The total-bound fraction on U87.CD4.CXCR4 cells resulted in 7.1±0.5% of administered activity (AMD3100 blocking by 58%) and 2.46±0.13% on MM.1S cells (AMD3100 blocking by 31%). [18F]AlF-NOTA-SC showed CXCR4 specific tumor uptake and excellent pharmacokinetic profile. By outperforming [18F]FDG, [18F]AlF-NOTA-SC is a promising candidate for clinical translation."

Hematological Malignancies • Multiple Myeloma • Oncology • CD4 • CXCL12 • CXCR4

Modeling the SDF-1/CXCR4 protein using advanced artificial intelligence and antagonist screening for Japanese anchovy. (PubMed, Front Physiol) - "We earlier found that this signaling is largely conserved in the Japanese anchovy (Engraulis japonicus, EJ), and a mere treatment of CXCR4 antagonist, AMD3100, leads to germ cell depletion and thereafter gonad sterilization...Three potential candidates, AMD3465, WZ811, and LY2510924, were selected and in vivo validation was conducted using Japanese anchovy embryos...The other three antagonists showed various degrees of PGC dispersion, but no significant effect compared to their solvent control at tested concentrations was observed. Cumulatively, our results suggests that AMD3645 might be a better candidate for abnormal PGC migration in Japanese anchovy and warrants further investigation."

Journal • Metastases • CXCL12 • CXCR4

CXCL12-CXCR4 mediates CD57 CD8 T cell responses in the progression of type 1 diabetes. (PubMed, J Autoimmun) - "Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57 CD8 T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57 CD8 T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes."

Journal • Diabetes • Immune Modulation • Immunology • Metabolic Disorders • Oncology • Type 1 Diabetes Mellitus • B3GAT1 • CD8 • CXCL12 • CXCR4 • STAT3

Biological and mutational analyses of CXCR4-antagonist interactions and design of new antagonistic analogs. (PubMed, Biosci Rep) - "To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The newly designed analogs displayed significantly increased binding to CXCR4, which supports the notion that negatively charged residues of CXCR4 can engage in interactions with moieties of positive charge of the antagonistic ligands. The results from these mutational, modeling and new analog design studies shed new insight into the molecular mechanisms of different types of antagonists in recognizing CXCR4 and guide the development of new..."

Biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • Oncology

Fabrication of pellets via extrusion-spheronisation for engineered delivery of Famotidine through specialized straws for Paediatrics. (PubMed, Ann Pharm Fr) - "Finally, the fast-disintegrating pellets demonstrated excellent in vitro performance and relative ease of manufacturing as compared to other solid dosage forms. Furthermore, the developed specialized straw can be used as a convenient and attractive drug delivery device for pediatrics."

Journal • Gastrointestinal Disorder • Pediatrics

Formulation development, in vivo bioequivalence and pediatric PBPK modeling studies of taste-masked ciprofloxacin chewable tablets. (PubMed, Sci Rep) - "A taste-masked chewable tablet of ciprofloxacin using ion exchange resin Kyron T-134 for enhancing compliance for the paediatric population was developed. The formulation F-9 was found to be bioequivalent with a geometric mean ratio of C, T, AUC, and AUC within 90% CI. It was concluded that quality by design approach can successfully be applied to optimize the drug resin ratio and PBPK modeling is a successful predictive tool for estimating the pharmacokinetics of ciprofloxacin HCl in the paediatric population."

Journal • Preclinical • Pediatrics

New Insights into the Determinants of Specificity in Human Type I Arginase: Generation of a Mutant That Is Only Active with Agmatine as Substrate. (PubMed, Int J Mol Sci) - "Now, the specificity of arginase is completely altered, generating a chimeric species that is only active with agmatine as a substrate, by substituting I129T, N130Y, and T131A together with the elimination of residues P132, L133, and T134...Evidence was also obtained to define the loop B as a structural determinant for substrate affinity. Concretely, the double mutation D181T and V182E generate an enzyme with an essentially unaltered k value, but with a significantly increased K value for arginine and a significant decrease in affinity for its product ornithine."

Journal • ARG1

The contributory roles of the CXCL12/CXCR4/CXCR7 axis in normal and malignant hematopoiesis: A possible therapeutic target in hematologic malignancies. (PubMed, Eur J Pharmacol) - "Plerixafor, BKT140, LY2510924, PF-06747143, ulocuplumab, and NOX-A12 are among the most well-known CXCR4 and CXCL12 modulators that their therapeutic efficacies have been evaluated in different pre-clinical and clinical studies of hematologic malignancies. To have an overview of the importance of CXCL12/CXCR4 and CXCL12/CXCR7 axes in the pathogenesis of leukemia and to gather information about the latest advances as well as challenges in targeting these axes in clinical settings, the present review has begun with a discussion about how aberrant expression of CXCL12/CXCR4 and CXCL12/CXCR7 pathways might regulate leukemogenesis and ended by outlining the key news of preclinical and clinical investigations in leukemia treatment."

Journal • Review • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • ACKR3 • CXCL12 • CXCR4

Efficacy of 'Foundations', a Digital Mental Health App to Improve Mental Well-Being, during COVID-19: A Proof-of-Principle Randomised Controlled Trial. (PubMed, JMIR Mhealth Uhealth) - "This study provides proof-of-principle that the digital mental health app, Foundations, can improve measures of mental well-being, anxiety, resilience, and sleep within 2 weeks of use, with greater effects after 4 weeks. It therefore offers potential as a scalable, cost-effective and accessible solution to enhance mental well-being, even during times of crisis such as the COVID-19 pandemic."

Clinical • Journal • CNS Disorders • General Anxiety Disorder • Infectious Disease • Insomnia • Mental Retardation • Mood Disorders • Novel Coronavirus Disease • Psychiatry • Sleep Disorder

Initial report of a phase I study of LY2510924 with idarubicin and cytarabine (IA) in relapsed/refractory (R/R) AML. (ASCO 2018) - P1b; "Combination of LY2510924 with IA is safe in R/R AML pts. Dose-escalation to 40 mg of LY2510924 is planned to achieve > 90% blockade of CXCR4 receptor occupancy, followed at the expansion phase of the study at recommended phase 2 dose level."

P1 data • Acute Myelogenous Leukemia

Preclinical Evaluation of [Cu]NOTA-CP01 as a PET Imaging Agent for Metastatic Esophageal Squamous Cell Carcinoma. (PubMed, Mol Pharm) - "We developed a copper-64 (t = 12.7 h, 19% beta) labeling route of NOTA-CP01 derived from LY2510924, a cyclopeptide-based CXCR4 potent antagonist, in an attempt to noninvasively visualize CXCR4 expression in metastatic ESCC...The immunofluorescence and immunohistochemistry confirmed the positive expression of CXCR4 in the EC109 tumor and ESCC and metastatic lymph nodes of patients, respectively. We concluded that [Cu]NOTA-CP01 possessed a very high target engagement for CXCR4-positive ESCC and could be a potential candidate in the clinical detection of metastatic ESCC."

Journal • Preclinical • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CXCR4

High-Contrast CXCR4-Targeted F-PET Imaging Using a Potent and Selective Antagonist. (PubMed, Mol Pharm) - "We, therefore, aimed to develop a high-contrast CXCR4-targeting radiotracer by incorporating a hydrophilic linker and trifluoroborate radioprosthesis to LY2510924, a known CXCR4 antagonist...Based on high tumor-to-organ ratios, [F]BL08 may prove a valuable new tool for CXCR4-targeted PET imaging with potential for translation. The use of a PepBF moiety is a new approach for the orthogonal conjugation of organotrifluoroborates for F-labeling of peptides."

Journal • Burkitt Lymphoma • Hematological Malignancies • Lymphoma • Oncology • CXCR4

At the bedside: Profiling and treating patients with CXCR4-expressing cancers. (PubMed, J Leukoc Biol) - "To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization)...These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb)...Biol. xx: xx-xx; 2020."

Clinical • Journal • Review • Oncology • Solid Tumor

C-terminal-modified LY2510924: a versatile scaffold for targeting C-X-C chemokine receptor type 4. (PubMed, Sci Rep) - "The hepatic accumulation of Ga-FRM001 was preferentially and significantly reduced by co-injecting a CXCR4 antagonist, AMD3100. The C-terminal-modified LY2510924 would constitute a versatile scaffold to develop CXCR4-targeting probes or therapeutics for tumor imaging or therapy."

Journal • Oncology

Creation of a robust and R-selective ω-amine transaminase for the asymmetric synthesis of sitagliptin intermediate on a kilogram scale. (PubMed, Enzyme Microb Technol) - "The best variants (M1 + M122H and M1+T134 G) were obtained using a semi-rational protein design after screening. >99 %) was produced within 30 h when 50 kg PTfpB was used as the substrate. Furthermore, the space-time yield reached ≈32 g/(L·d)."

Journal

Manipulating immune system using nanoparticles for an effective cancer treatment: Combination of targeted therapy and checkpoint blockage miRNA. (PubMed, J Control Release) - "In this study, PD-L1 inhibition therapy and BRAF-targeted therapy, which showed clinical benefit, were combined in a CXCR4-targeted nanoparticle co-delivering dabrafenib (Dab), a BRAF inhibitor, and miR-200c which can down-regulate PD-L1 expression. The cationic PCL-PEI core containing Dab- and miR-200c- were coated with poly-L-glutamic acid conjugated with LY2510924, a CXCR-4 antagonist peptide, (PGA-pep) to obtain miR@PCL-PEI/Dab@PGA-pep nanoformulation...More importantly, effector T cells were increasingly infiltrated into the tumor, whereas the immunosuppressive factors like PD-L1 expression and regulatory T cells were significantly reduced. They, all together, promote the immune responses against the tumor, indicating the therapeutic efficiency of the current strategy in cancer treatment."

Checkpoint inhibition • IO Biomarker • Journal • Oncology • BRAF • CD8 • CXCR4 • MIR200 • MIR200C

Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions. (PubMed, Pharmacol Res) - "It is therefore of great interest to investigate CXCR4/CXCR7/CXCL12 modulators in clinical development, with several CXCR4 and CXCL12 modulators such as plerixafor, ulocuplumab, balixafortide, and olaptesed pegol having already reached this stage...Contrary to CXCR4 and CXCL12 modulators, CXCR7 modulators have, thus far, not been extensively studied. Therefore, more (pre)clinical investigations are needed."

Journal • Review • Cardiovascular • CNS Disorders • Genito-urinary Cancer • Glioblastoma • Immunology • Multiple Sclerosis • Myocardial Infarction • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • CXCR4

CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-b Signaling. (PubMed, Cancers (Basel)) - "In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-b in stromal cells or TGF-b-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-b signaling."

Clinical • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study. (PubMed) - Invest New Drugs - "Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Baseline CXCR4(+) CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS."

Biomarker • Journal • Biosimilar • Lung Cancer • Oncology • Small Cell Lung Cancer

[68Ga]Ga/[177Lu]Lu-BL01, a Novel Theranostic Pair for Targeting C-X-C Chemokine Receptor 4. (PubMed, Mol Pharm) - "[68Ga]Ga-BL01 and [177Lu]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies."

Journal • Burkitt Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. (PubMed, Theranostics) - "Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway. We further identified FDA approved clinical drug procaterol can serve as an effective CDK12 inhibitor, leading to dramatic restriction of cancer cell proliferation and tumor growth in human gastric cancer cells and PDXs. Our data highlight the potential of CDK12/PAK2 as therapeutic targets for patients with gastric cancer, and we propose procaterol treatment as a novel therapeutic strategy for human gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDK12