LY2510924 acetate

LY2510924 acetate is the acetate salt form of LY2510924（CAS No.: 1088715-84-7）. LY2510924 is a high-affinity CXCR4（C‑X‑C chemokine receptor type 4）antagonist, essentially a cyclic nonapeptide, with the structural sequence: Cyclo[Phe‑Tyr‑Lys(iPr)‑D‑Arg‑2‑Nal‑Gly‑D‑Glu‑Lys(iPr)‑NH₂]. By competitively binding to the CXCR4 receptor, it blocks binding of the natural ligand SDF‑1（CXCL12）and downstream signal transduction. LY2510924 mainly regulates the PI3K/Akt and Ras/Raf/MAPK（ERK）cascades downstream of the SDF‑1/CXCR4 axis, and can inhibit SDF‑1-induced p‑ERK and p‑Akt phosphorylation in a concentration-dependent manner. In a human CXCR4 recombinant system, the measured IC₅₀ = 0.36 ± 0.07 nM, and the IC₅₀ for mouse CXCR4 = 17.53 ± 8.25 nM, with human affinity approximately 35-fold higher than mouse affinity.

In cell experiments, it is commonly used in U937, Namalwa, A498, A549, HCT116, HeLa, U87.CD4.CXCR4, MM.1S, and CCR5/ACKR3-expressing cells, etc. The working concentrations in competitive binding, signal transduction, and migration assays are roughly distributed between 0.01 nmol/L–10 μmol/L, and it is often used as a self-block control for the [¹⁸F]AlF‑NOTA‑SC PET probe.

Animal experiments mostly use subcutaneous or tail-vein xenograft tumor models for “therapeutic intervention” rather than model establishment, including subcutaneous xenografts of non-Hodgkin lymphoma Namalwa, renal cancer A498, lung cancer A549, colon cancer HCT116, as well as an MDA‑MB‑231 breast cancer experimental lung metastasis model（including pre-dosing 24 h before tumor inoculation and initiating dosing 24 h after inoculation, to evaluate the effects on metastatic initiation and colonization）. Common dosing regimens include subcutaneous injection in SCID/NMRI mice at 0.1, 0.3, 1, 3 mg/kg BID or 0.6 mg/kg QD, among which 3 mg/kg BID can significantly inhibit tumor growth or reduce the number of metastatic lesions in multiple solid tumor and MDA‑MB‑231 lung metastasis models.

In terms of PK, subcutaneous dosing of 0.5–1 mg/kg in SD rats, Beagle dogs, and Cynomolgus monkeys（IV/SC crossover）showed that the terminal half-lives of LY2510924 in dogs and monkeys were approximately 3.2 h and 3.3 h, respectively. In a clinical phase I study（advanced solid tumors, 45 cases, NCT01391130 series）, daily subcutaneous injection was administered in 28-day cycles, with dose escalation to 1.0 / 2.5 / 5.0 / 10 / 20 / 30 mg/day. The MTD was 20 mg/day（2 cases of G3 neutrophil increase DLT occurred in the 30 mg/day cohort）, the recommended phase II dose（RP2D）was 20 mg/day, and the biologically effective dose（BED）was 2.5 mg/day（at this dose, receptor occupancy was ≥96.9%, accompanied by CD34⁺ cell mobilization and a significant increase in ANC）. Under 20 mg/day conditions, on day 28 the mean Cmax ≈ 716 ng/mL, AUCₜ ≈ 3,800 ng·h/mL, and t₁/₂≈ 9.16 h, and plasma exposure was approximately 4 times the tumor-inhibitory IC₅₀ in the NHL xenograft model. In a preclinical study of PET imaging with the LY2510924 derivative [¹⁸F]AlF‑NOTA‑SC, the U87.CD4.CXCR4 xenograft SUVmean = 3.04 ± 0.65, and the MM.1S xenograft SUVmean = 1.95 ± 0.11, both of which could be competitively blocked by AMD3100（5 mg/kg i.p.）.

References:

[1] Galsky MD, Vogelzang NJ, Conkling P, Raddad E, Polzer J, Roberson S, Stille JR, Saleh M, Thornton D. A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer. Clin Cancer Res. 2014 Jul 1;20(13):3581-8. doi: 10.1158/1078-0432.CCR-13-2686. Epub 2014 Apr 11. Erratum in: Clin Cancer Res. 2014 Aug 15;20(16):4414. PMID: 24727324.

[2] Peng SB, Zhang X, Paul D, Kays LM, Gough W, Stewart J, Uhlik MT, Chen Q, Hui YH, Zamek-Gliszczynski MJ, Wijsman JA, Credille KM, Yan LZ. Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. Mol Cancer Ther. 2015 Feb;14(2):480-90. doi: 10.1158/1535-7163.MCT-14-0850. Epub 2014 Dec 12. PMID: 25504752.

[3] Spahn MA, Loy TV, Celen S, Koole M, Deroose CM, Cawthorne C, Vanduffel W, Schols D, Bormans G, Cleeren F. Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924. Eur J Nucl Med Mol Imaging. 2025 Apr;52(5):1723-1738. doi: 10.1007/s00259-024-07025-w. Epub 2024 Dec 11. PMID: 39658737; PMCID: PMC11928405.