LY2510924

Preclinical studies demonstrate that CXCR4 antagonists (e.g., plerixafor, LY2510924) suppress metastasis and, when combined with immune checkpoint inhibitors, can reverse the "cold" immune phenotype of microsatellite-stable CRC. We also discuss recent advances in the regulation of CXCL12/CXCR4 expression, the role of related receptors such as CXCR7, and emerging strategies targeting this axis for therapeutic intervention. Collectively, current evidence supports the CXCL12/CXCR4 axis as a promising biomarker and therapeutic target in metastatic CRC, and further elucidation of its regulatory network may facilitate the development of more effective precision treatment strategies.

Antagonistic peptides AMD3100 (Plerixafor), LY2510924, and POL6326, as well as their therapeutic potential. Future research on Mavorixafor will focus on two main areas: personalized medicine development, new delivery systems and their broad medical applications extending beyond oncology. As a potential CXCR4 antagonist, Mavorixafor shows promise as a transformative tool in cancer care because it regulates the tumor microenvironment (TME) while increasing the degree of therapeutic benefits.

We developed a new C-X-C chemokine receptor 4 (CXCR4)-targeting radiolabeled peptide, [68Ga]Ga/[177Lu]Lu-BL34, using a novel and potent cyclic peptide based on structure-activity relationship studies of LY2510924... We report a new CXCR4-targeting pharmacophore that can be used as a radiotheranostic. [68Ga]Ga-BL34 and [177Lu]Lu-BL34 showed excellent imaging and therapeutic properties in preclinical studies and are promising candidates for clinical translation.

[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.

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.

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.

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.

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.

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.

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.

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.

[68Ga]Ga-BL01 and [177Lu]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.